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Published: 1 February 2004
Immunological Reviews, Volume 197, pp 75-88; https://doi.org/10.1111/j.0105-2896.2004.0103.x

Abstract:
Many of the stromal-derived signals and factors that regulate B lymphopoiesis have been identified. We review recent evidence from our laboratory that shows that there are at least three phases during B-cell development when cells direct their own maturation, independent of stromal cells. Following the expression of the preB-cell receptor (preBCR), cells acquire the ability to proliferate in low levels of interleukin-7 (IL-7), which acts as a self-selecting mechanism to expand cells that have successfully expressed a preBCR in environments that are non-permissive to preBCR- cells. Second, the preBCR is required for a contact-mediated event between B-cell progenitors. Disruption at this stage prevents the further maturation of progenitors to the lipopolysaccharide (LPS)-responsive stage. Finally, the transition from IL-7 receptor to mature antigen receptor-based signaling is enhanced by a novel member of the tachykinin family, hemokinin-1. This series of maturation, survival, and differentiation signals is generated by B-lineage cells as they progress through developmental checkpoints on the way to becoming functionally mature cells.
Emmanuelle Gaudin, Manuela Rosado, , Angela McLean,
Published: 1 February 2004
Immunological Reviews, Volume 197, pp 102-115; https://doi.org/10.1111/j.0105-2896.2004.0095.x

Abstract:
In adult mice, the number of B lymphocytes remains constant under homeostatic control, in spite of the fact that B cells are produced continuously in numbers that largely exceed the number required to replenish the peripheral pools. It follows that each newly formed lymphocyte can only persist if another lymphocyte dies. In an immune system where the total number of cells is limited, cell survival is no longer a passive phenomenon but rather a continuous active process where each lymphocyte must compete with other lymphocytes to survive. Consequently, the number and the life expectancy of a B-cell clone vary according to the presence or absence of competitor populations. This process of lymphocyte competition is likely controlled by a common need for resources that are in limited supply. The number of peripheral B-cells varies according to the availability of B-cell receptor (BCR) ligands. Indeed, it is possible to modify steady-state B-cell numbers by antigen manipulation. Moreover, conventional self-reactive B cells can undergo positive selection. We showed that the fate of a self-reactive B cell is determined by the quantity of self-antigens, the number of antigen-specific receptors engaged, and its overall antigen-binding avidity rather than the affinity of individual BCRs.
Published: 1 December 2008
Immunological Reviews, Volume 226, pp 10-18; https://doi.org/10.1111/j.1600-065x.2008.00701.x

Abstract:
The interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily was first defined in 1998 as a family of proteins that contain the Toll-IL-1 receptor domain. At that time, there were a number of orphan receptors in the IL-1R branch, and the TLRs had yet to be shown to be key innate immune receptors that sense microbial products. We now know a great deal more about this superfamily, with the description of novel IL-1 family members such as IL-1F6 signaling via IL-1Rrp2 and IL33 signaling via ST2. Remarkable progress has been made in our understanding of the functions of the TLRs, leading to a renaissance of interest in innate immunity. The importance of IL-1 is also being rediscovered, with the observation that Nalp3 is a key regulator of caspase-1, the enzyme that processes pro-IL-1beta into the mature cytokine. This area has therefore proved very fruitful in terms of improving our knowledge of the molecular basis for innate immunity and inflammation, and we can anticipate further discoveries in the coming years.
Lesley Pasman,
Published: 30 August 2017
Immunological Reviews, Volume 279, pp 52-62; https://doi.org/10.1111/imr.12576

The publisher has not yet granted permission to display this abstract.
Published: 1 March 2009
Immunological Reviews, Volume 228, pp 212-224; https://doi.org/10.1111/j.1600-065x.2008.00744.x

Abstract:
Activation of immune cells to mediate an immune response is often triggered by potential \u27danger\u27 or \u27stress\u27 stimuli that the organism receives. Within the mitogen-activated protein kinases (MAPKs) family, the stress-activated protein kinase (SAPK) group was defined as group of kinases that activated by stimuli that cause cell stress. In the immune cells, SAPKs are activated by antigen receptors (B- or T-cell receptors), Toll-like receptors, cytokine receptors, and physical-chemical changes in the environment among other stimuli. The SAPKs are established to be important mediators of intracellular signaling during adaptive and innate immune responses. Here we summarize what is currently known about the role of two sub-groups of SAPKs - c-Jun NH(2)-terminal kinase and p38 MAPK-in the function of specific components of the immune system and the overall contribution to the immune response
Yong-Jun Liu, Christophe Arpin
Published: 1 April 1997
Immunological Reviews, Volume 156, pp 111-126; https://doi.org/10.1111/j.1600-065x.1997.tb00963.x

Abstract:
Using a set of surface markers including IgD and CD38, human tonsillar B cells were classified into discrete subpopulations. Molecular and functional analysis allowed us to identify: i) two sets of naive B cells (Bm1 and Bm2); ii) germinal center founder cells (Bm2'); iii) an obscure population of germinal center B cells, displaying a high load of somatic mutations in IgV genes, C mu to C delta switch and preferential Ig lambda light chain usage: these cells may represent the precursors of normal and malignant IgD-secreting plasma cells; iv) the centroblasts (Bm3) in which somatic mutation machinery is activated; v) the centrocytes (Bm4) in which isotype switch occurs; vi) the memory B cells. The characterization of these subpopulations showed that: i) programmed cell death is set before somatic mutations, possibly providing an efficient way for affinity maturation; ii) only high affinity centrocytes are allowed to switch isotype; iii) CD40-ligation inhibits plasmacytic differentiation of mature B lymphocytes; iv) memory B cells preferentially differentiate into plasma cells; v) IgD isotype switch occurs in normal B cells; vi) receptor editing may be induced by somatic mutations in germinal centers. We also characterized two types of antigen-presenting cells in germinal centers: follicular dendritic cells that select high affinity B cells, and a new subset of germinal center dendritic cells that activate germinal center T cells.
Bruce A. Jacobson, Thomas L Rothstein, Ann Marshak-Rothstein
Published: 1 April 1997
Immunological Reviews, Volume 156, pp 103-110; https://doi.org/10.1111/j.1600-065x.1997.tb00962.x

Abstract:
MRL/lpr (Fas-deficient) mice develop an autoimmune syndrome associated with excessive production of autoantibodies. A significant portion of these autoantibodies are IgG2a molecules specific for many of the autoantigens recognized by the sera of patients with systemic lupus erythematosus. In addition, MRL/lpr mice make exceedingly high titers of IgG or IgA rheumatoid factors (RF) specific for autologous IgG2a. The microenvironment of the IgG2a-producing B cells as well as the prototypic RF autoantibodies was determined by a combination of immunohistochemical and in situ hybridization techniques. In contrast to the antibody-producing cells present in mice responding to conventional foreign antigens, both IgG2a+ and RF+ B cells were found to be densely clustered in the T-cell-rich inner periarteriolar lymphatic sheath of the spleen. These results suggest that conventional antibody and autoantibody production in MRL/lpr mice may be mechanistically distinct processes.
Valery Renard, Anna Cambiaggi, , , Lucia Olcese, Sylvain Olivero, Magali Bouchet,
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 205-221; https://doi.org/10.1111/j.1600-065x.1997.tb00953.x

Abstract:
NK-cells are large granular lymphocytes, which are capable of exerting two major types of effector function, cell cytotoxicity and lymphokine secretion. NK-cells can exert cell cytotoxicity in one of two ways. First, NK-cells are able to recognize and to induce the lysis of antibody-coated target cells during antibody-dependent cell cytotoxicity (ADCC). Second, during natural cytotoxicity NK-cells are also able to recognize and to induce the lysis of a variety of target cells, including primarily virus-infected cells as well as tumor cells. Recently, a novel mechanism has been elucidated which controls NK-cell-activation programs and which is based on the cell surface expression of killer-cell inhibitory receptors (KIR). We will review here the molecular dissection of this inhibitory signalling pathway which utilizes immunoreceptor tyrosine-based inhibition motifs (ITIM) expressed in KIR intracytoplasmic domain. We will also show that this strategy used by NK-cells to regulate their effector functions is a general decision mechanism which exists not only in T- and B-lymphocytes, but also in a variety of other hematopoietic cells.
, Juan J. Perez-Villar, , Antonio Rodriguez, Ignacio Melero, Teresa Bellon, Manuel Llano, Francisco Navarro
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 165-174; https://doi.org/10.1111/j.1600-065x.1997.tb00949.x

The publisher has not yet granted permission to display this abstract.
, Brian Corliss, Joseph H. Phillips
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 145-154; https://doi.org/10.1111/j.1600-065x.1997.tb00947.x

The publisher has not yet granted permission to display this abstract.
, , William P. Clark, Marta Peruzzi, Sumati Rajagopalan, Susana Rojo, Nicolai Wagtmann, Christine C. Winter
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 135-144; https://doi.org/10.1111/j.1600-065x.1997.tb00946.x

Abstract:
NK cells selectively kill target cells that fail to express self-MHC class I molecules. This selective killing results from a balance between inhibitory NK receptors specific for MHC class I molecules and activating receptors that are still largely unknown. Isolation of molecular clones for the human killer cell inhibitory receptors (KIR) revealed that KIR consist of a family of molecules with Ig ectodomains and cytoplasmic tails of varying length. Soluble complexes of KIR and HLA-C molecules established that KIR recognizes and binds to its ligand as an autonomous receptor. A functional expression system in human NK clones demonstrated that a single KIR can provide both recognition of MHC class I and delivery of a dominant negative signal to the NK cell. Functional evidence has been obtained for a role of the tyrosine phosphatase SHP-1 in KIR-mediated inhibition. The presence of a conserved motif used to recruit and activate SHP-1 in the cytoplasmic tail of KIR and of the mouse Ly-49 inhibitory receptor (otherwise structurally unrelated to KIR) represents an interesting case of evolutionary convergence. Furthermore, the motif led to the identification of other receptors with inhibitory potential, including a type I Ig-like receptor shared by mouse mast cells and NK cells.
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 127-133; https://doi.org/10.1111/j.1600-065x.1997.tb00945.x

Abstract:
Human NK cells express clonally distributed receptors specific for HLA-A, -B and -C molecules. These receptors belong to the immunoglobulin superfamily and can be functionally distinguished as inhibitory or stimulatory. Inhibitory receptors block NK-cell-mediated cytotoxicity upon binding to HLA class I ligands. This function is mediated by phosphorylation of cytoplasmic tyrosines, which recruit the protein tyrosine phosphatase SHP-1. Stimulatory receptors also bind HLA class I, lack cytoplasmic tyrosine-based motifs, and trigger NK cytotoxicity and proliferation. Both types of receptor are characterized by a limited diversity allowing for recognition of distinct class I supertypic epitopes. This limited diversity is counterbalanced by the expression of different combinations of inhibitory and stimulatory receptors with self and/or non-self HLA class I specificities on distinct NK cell clones. This peculiar strategy allows NK cells to detect loss of MHC class I molecules on autologous transformed and virally infected cells with maximal sensitivity.
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 105-117; https://doi.org/10.1111/j.1600-065x.1997.tb00943.x

Abstract:
Human NK cells express several specialized inhibitory receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on normal cells. The lack of expression of one or more HLA class I alleles leads to NK-mediated target cell lysis. Receptors specific for groups of HLA-C (p58), HLA-B (p70) and HLA-A (p140) alleles belong to the Ig superfamily with two or three Ig-like domains in their extracellular portion, and a long cytoplasmic tail containing ITIM motifs and associated with a non-polar transmembrane portion. In contrast, the CD94/ NKG2-A receptor complex is composed of type II proteins with a C-type lectin domain which displays a more broad specificity for different class I alleles. Recently, activatory forms of the HLA-C-specific receptors have been identified in some donors. They are virtually identical to the inhibitory forms in their extracellular portions, but display a short cytoplasmic tail lacking ITIM motifs associated with a Lys-containing transmembrane portion (p50). A subset of activated T-lymphocytes, primarily CD8+ and oligoclonal or monoclonal in nature, express NK-type class I-specific receptors. These receptors exert an inhibitory activity on T-cell receptor-mediated functions and may provide an important mechanism of down-regulation of T-cell responses.
, Jack Brennan,
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 67-77; https://doi.org/10.1111/j.1600-065x.1997.tb00940.x

Abstract:
The Ly-49 family consists of at least nine members, of which Ly-49A and C have been found to be NK-cell inhibitory receptors specific for class I MHC. The functions of other Ly-49 molecules are still unclear. Further analysis of Ly-49 is complicated by the cross-reactivities of some anti-Ly-49 antibodies initially thought to be specific for individual Ly-49 molecules. Studies on the role of Ly-49 in hybrid resistance as well as on allelic exclusion are also complicated by our recent finding that a novel Ly-49CB6 gene is the likely allelic form of Ly-49CBALB as opposed to a previously reported highly related but distinct gene in B6 mice. In cell-cell binding assays, only Ly-49A and C show significant binding to class I MHC. Ly-49A and C also bind some polysaccharides, and carbohydrates on class I MHC seem to be important for its binding to Ly-49. However, this interaction involves not only the carbohydrate recognition domain of Ly-49 but also a part of the stalk region, suggesting that both carbohydrates and peptide backbone of class I MHC may be recognized by Ly-49. It is likely that additional Ly-49 molecules yet to be identified function as NK-inhibitory receptors specific for class I MHC.
, Jonas Sundback, Mats Y. Olsson-Alheim, Maria Johansson, , Claes Ohien, , , Klas Karre
Published: 1 February 1997
Immunological Reviews, Volume 155, pp 11-28; https://doi.org/10.1111/j.1600-065x.1997.tb00936.x

The publisher has not yet granted permission to display this abstract.
Samuel Strober, Lirong Cheng, Defu Zeng, Raju Palathumpat, Sussan Dejbakhsh-Jones, Phillip Huie, Richard K Sibley
Published: 1 February 1996
Immunological Reviews, Volume 149, pp 217-230; https://doi.org/10.1111/j.1600-065x.1996.tb00906.x

Y. Modigliani, A. Bandeira,
Published: 1 February 1996
Immunological Reviews, Volume 149, pp 155-174; https://doi.org/10.1111/j.1600-065x.1996.tb00903.x

Abstract:
Current models of tolerance to peripheral, tissue-specific antigens contain some major caveats. First, they consider peripheral tolerance independently from intrathymic T cell selection, a dichotomy that is challenged by observations on TE-induced tolerance. Second, they do not account for the fact that vertebrates are more readily tolerised in development than in adult life. Third, they do not explain the fact that embryonic/neonatal tolerance to foreign tissues can only be induced by HC or TE. A model of thymic selection and peripheral tolerance is developed here that resolves those problems, by assuming two classes of T cell effector functions, one being regulatory and the other aggressive. Three postulates are required: (1) both epithelial and hemopoietic cellular compartments of the thymic stroma can support both positive and negative selection of T cells, but with vastly different avidity requirements and efficiency; (2) positively selected T cells with the highest avidity that escape deletion are activated intrathymically and irreversibly committed for regulatory effector functions; (3) the functional phenotype of all other thymic emigrants is determined in the periphery upon encounter with antigen. Functional commitment in the periphery depends on the maturity stage (RTE or PMR) of the immunocompetent cell, on the nature of the antigen-presenting cells, and on the effector classes of other T lymphocytes interacting on the same presenting cell. This model explains a number of observations on experimental autoimmune disease and transplantation tolerance, and it contains several readily testable predictions.
Nicole Le Douarin, Catherine Corbel, Antonio Bandeira, , Yves Modigliani, , Josselyne Salaun
Published: 1 February 1996
Immunological Reviews, Volume 149, pp 35-53; https://doi.org/10.1111/j.1600-065x.1996.tb00898.x

Abstract:
The avian embryo has provided an appropriate model to study the ontogeny of the primary lymphoid organs, thymus and bursa of Fabricius. By using the quail-chick marker system the embryonic origin of the highly intricate cell components which form these organs could be traced back to the initial endodermal, mesodermal and ectodermal germ layers. The timing and dynamics of the incoming and outcoming flows of hemopoietic cells which characterize their lymphopoietic activity could be revealed in both quail and chick embryos. This knowledge served as a basis for an investigation on the role of the epithelial component of the thymus (derived from the pharyngeal endoderm) on tolerance to tissue graft and, by extension, tolerance to self. When this work was undertaken, the prevailing view was that exposure of the developing immune system to foreign antigens in the embryo allows them to be assimilated to self components in the mature animal. In fact, this was found to be true for allogeneic grafts between MHC-distinct chickens, of certain tissues, such as for instance wing tissues. However, in heterospecific transplantations, i.e. when a limb bud was grafted from quail to chick embryos, the chick host acutely rejected the foreign limb soon after birth. In contrast, grafts of the quail thymic epithelial (TE) rudiment resulted in the development of a chimeric thymus in which the foreign epithelial component was not only tolerated but able to induce full tolerance of the grafted wing from the same donor. By monitoring the amount of quail TE implanted we showed in addition that only part of the peripheral T-cell population had to differentiate in the context of the quail epithelial cells to induce tolerance to quail tissues. This pointed to the generation in the thymus of regulatory T cells, coexisting with specific anti-quail reactive T cells, but able to inhibit them from reacting against the quail wing antigenic determinants. A mammalian model was then devised to further study this mechanism of tolerance that we have qualified as "dominant" by opposition to the current model based on either clonal elimination or anergy which can be considered as recessive or passive. Nude mice of MHC type A were grafted with TE of E10 type B embryos. They became reconstituted for T-cell function but tolerant for B skin allografts. Spleen cells from such tolerant animals injected to naive A nude mice reconstituted T cell function in the recipient and transferred the tolerance to B skin grafts. Reducing the number of donor cells resulted in the segregation of the two phenomena. For low numbers the recipients were restored but not tolerant, thus showing the coexistence in the tolerant donor of anti-B reactive T cells together with regulatory cells able to abolish their reactivity against B determinants. Other experiments demonstrated that TE-induced tolerance does not rely on clonal deletion or anergy. This was shown on systems where elimination of cells directed toward superantigens was screened. It turned out that tolerance to skin grafts and superantigen T-cell deletion are unrelated phenomena. These observations strongly suggest that tolerance to self results at least in part from the interplay between cells potentially harmful for self component and others which exert a strong control on their reactivity. The latter cell type depends upon interactions of thymocytes with the endodermal component of the thymus.
, Elizabeth Adams, Sara E. Marshall, Joanna D. Davies,
Published: 1 February 1996
Immunological Reviews, Volume 149, pp 5-33; https://doi.org/10.1111/j.1600-065x.1996.tb00897.x

Abstract:
Over the last five years it has become increasingly clear that the peripheral immune system can maintain tolerance to both self and non-self antigens through a variety of mechanisms. Although clonal deletion may play an important part in limiting rapidly expanding responses, there are many examples where antigen reactive T cells remain. It has been proposed that tolerance is maintained in this situation either by the induction of anergy or by ongoing suppression. The phenomenon known as immune deviation, where non-inflammatory Th2 responses could suppress Th1 and positively reinforce themselves provided an attractive explanation for infectious tolerance, where tolerant T cells could guide further naive T cells also to tolerance. However, experiments to test this hypothesis in the models of CD4 and CD8 antibody-induced tolerance have given conflicting data, with no clear evidence of Th2 responses in tolerant mice. In this paper we review recent data that IL-4 plays a role in suppression, but that the source of IL-4 may not be the tolerant/suppressor T cell. We also discuss how infectious tolerance can operate on third party antigens if they are linked on the same antigen presenting cell and how CD4+ T cells can suppress CD8+ T-cell responses. Finally, we suggest a model of infectious anergy that is compatible with the available data
, Michael Croft, Caroline Dubey, Laura Haynes, Paul Rogers, Xiaohong Zhang,
Published: 1 April 1996
Immunological Reviews, Volume 150, pp 143-167; https://doi.org/10.1111/j.1600-065x.1996.tb00700.x

Arno Mullbacher, Kirsten Flynn
Published: 1 April 1996
Immunological Reviews, Volume 150, pp 113-127; https://doi.org/10.1111/j.1600-065x.1996.tb00698.x

Abstract:
Immunological T cell memory manifest itself in an accelerated second-set graft, or allogeneic tumour cell, rejection. Memory viral-immune cytotoxic T cells have shortened kinetics of induction in vivo and differentiate into more potent effector cells in vitro. The requirements for induction of memory T cells are less stringent than for naive T cells. Memory T cells can be activated by antigen (signal 1) or interaction with co-stimulatory molecules (CD28/CD80, signal 2) alone. Memory T cells are phenotypically distinguishable from naive T cells by a number of cell surface markers, but not from activated T cells. Persistence of antigen is not required for the maintenance of long-lived memory. Continuous stimulation by signal 2 alone and or longevity is sufficient to explain life-long persistence of T cell memory. All available data on memory T cells are consistent with a deterministic model of T cell memory formation, following a precise pathway of T cell differentiation.
Thomas M. Kundig, Martin F. Bachmann, , Hanspeter Pircher, Hans Hengartner, Rolf M. Zinkernagel
Published: 1 April 1996
Immunological Reviews, Volume 150, pp 63-90; https://doi.org/10.1111/j.1600-065x.1996.tb00696.x

Abstract:
Memory is a hallmark of the immune system. Considerable progress has been made towards understanding B cell memory, but T cell memory remains poorly understood and its nature is controversial. There is good evidence that B cell memory is driven by antigen, but the antigen dependence of T cell memory is still being debated. For several years we have investigated the nature, duration and antigen dependence of different aspects of CD8+ T cell memory and this review will discuss our findings as well as how and why they differ from some other results. As others, we find that antigen, due to proliferation of antigen-specific T cell clones, induces a shift in the T cell repertoire which remains detectable for years as an elevated cytotoxic T cell precursor frequency (CTLp) in lymphoid organs. Also in the absence of antigen, in vitro assays for T cell memory which invariably isolate memory T cells from these lymphoid organs therefore remain positive. In contrast, immunity against reinfection with a pathogen requires more than just elevated numbers of CTLp in lymphoid organs. Since reinfection usually takes place via peripheral nonlymphoid tissue, these CTLp have to a) efficiently extravasate and patrol through such tissues, and b) be immediately able to exert effector function in case of reinfection. Both functions, require a certain level of activation which critically depends on T cell stimulation by persisting antigen
Michael G. McHeyzer-Williams, John D. Altman, Mark M. Davis
Published: 1 April 1996
Immunological Reviews, Volume 150, pp 5-21; https://doi.org/10.1111/j.1600-065x.1996.tb00693.x

Abstract:
There is a great deal of interest in understanding how helper T cells differentiate in vivo and exert their regulatory role on a developing, immune response. Essential to development of protective immunity is the development of memory T cells. To study memory T cells in vivo we first need the means to identify and characterize these cells as they develop in their complex microenvironments. We have developed a method which allows us to directly purify both primary and memory helper T cells from the draining lymph nodes of mice as they respond to pigeon cytochrome c in vivo. Junctional sequences from these populations and from individual T cells show a strong selection for CDR3 length and residues characteristic of antigen binding. Overall these studies support a model of progressive clonal maturation with the memory T cell repertoire being more homogeneous than that of the primary response. There is some suggestion that affinity maturation may take place after repeated immunization, but on a more modest scale than that seen for antibodies. Finally we present the use of two new technologies that promise to greatly expand the analysis of immune responses in vivo. The use of flow cytometry with simultaneous detection of five and six fluorescence parameters helps to reliably resolve rare subsets of antigen-specific cells in order to understand the progression of their differentiation in vivo. Lastly, we have developed peptide/MHC tetramers as a new class of staining reagent that has wide applicability in the study of T cell responses in vivo.
Hidko Yagita, Shino Hanabuchi, Yoshthiro Asano, Toshiki Tamura, Htdeo Nariuchi, Ko Okumura
Published: 1 August 1995
Immunological Reviews, Volume 146, pp 223-239; https://doi.org/10.1111/j.1600-065x.1995.tb00691.x

Sujan Shresta, Jonathan W. Heusel, Debra M. MacIvor, Robin L. Wesselschmidt, , Timothy J. Ley
Published: 1 August 1995
Immunological Reviews, Volume 146, pp 211-221; https://doi.org/10.1111/j.1600-065x.1995.tb00690.x

Sinuhe Hahn, Roland Gehri, Peter Erb
Published: 1 August 1995
Immunological Reviews, Volume 146, pp 57-79; https://doi.org/10.1111/j.1600-065x.1995.tb00684.x

Abstract:
It is now well established that CD4+ T cells can express cytotoxic activity. This type of cell-mediated cytotoxicity is associated with the Th1-, but not with the Th2-phenotype. While the activation of CD4+ CTL is MHC class II-restricted, the effector phase, i.e. the target cell killing is unrestricted and antigen non-specific. In analogy to CD8+ CTL, CD4-mediated target cell death is by DNA fragmentation. However, the molecular mechanism of killing differs from CD8-mediated lysis. Thus, CD4+ CTL preferentially lyse their targets via Fas-Fas ligand interaction, whereas the major cytotoxic effect of CD8+ CTL is by granule exocytosis, i.e. perforin and granzymes. Although CD8+ CTL can also express the FasL, their lytic activity through interaction with Fas is of less importance. Likewise, some CD4+ CTL may also kill by perforin/granzymes activity, but this pathway is of minor significance. The aims of CD8- or CD4-mediated lysis are also different. Thus, the major task of CD8+ CTL which recognize and kill their targets in the context of MHC class I molecules, is the lysis of virally infected cells and battling against tumor cells. CD4+ CTL, on the other hand, have an immunomodulatory role. Thus, they preferentially eliminate activated MHC class II-positive cells, i.e. APC, be they monocytes/macrophages, B cells or T cells. They may lyse these cells in order to prevent an overreaction of the ongoing immune response or in order to remove potentially hazardous cells upon completion of the immune response. The Fas-FasL pathway is particularly suitable for this task as myeloid or lymphoid cells express Fas only if activated, while FasL is preferentially expressed on activated CD4+ Th1 cells. Moreover, activated T cells eliminate themselves by the Fas-mediated pathway. Whether this happens by fratricide only, or also by suicide or both is open. Moreover, CD4+ CTL are particularly suitable for killing tumor cells as well, as they are efficient effectors in bystander lysis in contrast to CD8+ CTL. On the other hand, the non-specific killing via Fas-FasL interaction, which is an important reason for the bystander lysis, may have unwanted effects in that cells which should not be eliminated could be killed. Such reactions affecting various organs and cells, e.g. the liver, thyroid or islet cells of the pancreas could be an explanation for certain autoimmune diseases.
William R. Clark, Craig M. Walsh, Alison A. Glass, Fumitaka Hayashi, Mehrdad Matloubian, Rafi Ahmed
Published: 1 August 1995
Immunological Reviews, Volume 146, pp 33-44; https://doi.org/10.1111/j.1600-065x.1995.tb00682.x

Warren J. Leonard, Elizabeth W. Shores, Paul E. Love
Published: 1 December 1995
Immunological Reviews, Volume 148, pp 97-114; https://doi.org/10.1111/j.1600-065x.1995.tb00095.x

Abstract:
To examine the role of gamma c in lymphoid development, we have analyzed mice in which the gamma c gene was specifically inactivated by homologous recombination. These mice also serve as an animal model of human X-linked severe combined immunodeficiency (XSCID). Interestingly, gamma c knockout mice exhibited a somewhat different phenotype than humans with XSCID. Absolute T-cell numbers are greatly diminished in young gamma c-/Y mice, but accumulate with age. gamma delta T cells and NK cells are absent in gamma c-/Y mice and conventional B cells are greatly diminished, yet substantial numbers of peritoneal B-1 cells are present. Since humans with XSCID have essentially no mature T cells, it is especially striking that T cells are readily apparent in gamma c-/Y mice. This observation indicates that in these mice, the gamma c-dependent block in T cell development is less severe than it is in humans. It is possible but unproven that thymic stromal derived lymphopoietin, TSLP, contributes to thymocyte development in these mice. Since B-cell numbers are normal in humans with XSCID, it is also striking that gamma c-/Y mice paradoxically exhibit greatly diminished numbers of B cells. This likely indicates that IL-7 signaling plays a critical role in pre-B cell maturation in mice but is less important in humans. Thus, the abnormalities observed in gamma c-/Y mice have provided clues to assist in dissecting the role of cytokines and their receptors in lymphoid development and have also identified interesting differences in the regulation of this process in mice and humans.
Published: 1 December 1995
Immunological Reviews, Volume 148, pp 19-34; https://doi.org/10.1111/j.1600-065x.1995.tb00091.x

Abstract:
The common cytokine receptor gamma chain (gamma c) plays a critical role in lymphoid development through its participation in the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Absence of gamma c results in abnormal lymphopoiesis and immunodeficiency, as evidence by X-linked severe combined immunodeficiency (SCIDX1) in man, and in the corresponding canine and murine models of SCIDX1. Comparison of the phenotypes of mutant mice made deficient for gamma c-dependent cytokines by gene targeting, allows us to define a hierarchy of gamma c-dependent cytokine function in lymphoid development. The participation of distinct cytokine/receptor interactions in the generation, maintenance and regulation of the immune system suggests that developmental steps may be controlled by individual cytokines. The mechanisms by which different cytokine signaling pathways achieve this process remain to be elucidated.
, Ulrike Muller, Sui Huang, Rolf M. Zinkernagel, Michel Aguet
Published: 1 December 1995
Immunological Reviews, Volume 148, pp 5-18; https://doi.org/10.1111/j.1600-065x.1995.tb00090.x

Abstract:
Mice lacking the receptor for type I interferon (IFN-alpha beta, A129 mice), for type II interferon (IFN-gamma, G129 mice) or for both receptors (AG129 mice) have been generated by embryonic stem cell mediated gene targeting and inter-crossing A129 x G129, respectively. The role of the two IFN systems in controlling a range of infections has been studied using these mice. Type I IFN is shown to be responsible for the immune defence against most viral infections tested (Lymphocytic Choriomeningitis Virus, Semliki Forest Virus, Theiler's Virus, Vesicular Stomatitis Virus), type II IFN seems to be of little importance. In Vaccinia Virus and Theiler's Virus infection, however, both IFN systems were found to play a nonredundant role. IFN-gamma was critical for the defence against intracellular bacteria (Mycobacterium, Listeria) and parasites (Leishmania), whereas IFN-alpha beta was not. IFN-alpha beta is produced by virus-infected cells within hours and plays an important role in preventing virus spread early. Production of IFN-gamma on the other hand needs activation of the immune system and plays a major role later, i.e. mostly during the immune response. Data obtained with the mice described here show that both IFN systems seem to have evolved to complement each other in the host defence against a wide variety of infectious agents.
, Delin Zhu, Catherine A. King, Lindsay J. Ashworth, Sanjeev Kumar, Robert E. Hawkins
Published: 1 June 1995
Immunological Reviews, Volume 145, pp 211-228; https://doi.org/10.1111/j.1600-065x.1995.tb00083.x

Abstract:
Idiotypic antigens are clearly defined tumor-associated protein antigens, which can induce protective immunity against lymphoma. Because each patient requires an individual vaccine, idiotypic antigens also provide ideal candidates for exploring the feasibility of replacing protein antigens by DNA vaccines. Component idiotypic variable region genes can be identified in patients' tumor biopsies and rapidly assembled as scFv sequences. These can be used to produce recombinant scFv protein in bacteria, or as direct naked DNA vaccines. A preliminary small trial of DNA vaccines for chemotherapy-resistant patients with lymphoma has begun. Intramuscular idiotypic DNA vaccination in a mouse model induces low levels of anti-idiotypic antibody in serum. Levels can be increased dramatically by coinjection of DNA plasmids encoding either IL-2 or GM-CSF, and specific proliferative anti-idiotypic T cells are induced. However protective immunity remains to be demonstrated, and a possible reason for this may lie in the continued secretion of idiotypic scFv antigen which blocks antibody activity by formation of immune complexes. Methods for regulating secretion of antigen are required before this category of tumor antigen can be fully exploited as a vaccine. The power of DNA technology should allow analysis and manipulation of pathways of antigen presentation to induce maximal therapeutic attack on neoplastic B cells. In addition, lymphoma presents a model for application of DNA technology to the wide range of human tumors known to harbor potential tumor antigens.
Philip O. Livingston
Published: 1 June 1995
Immunological Reviews, Volume 145, pp 147-166; https://doi.org/10.1111/j.1600-065x.1995.tb00080.x

Abstract:
Gangliosides are neuraminic acid containing glycosphingolipids that are anchored into the lipid bilayer of the plasma membrane by their lipophilic ceramide moiety. They are overexpressed on tissues of neuroectodermal origin, particularly in tumors such as melanomas, sarcomas, neuroblastomas and astrocytomas. With the ganglioside-KLH plus immunological adjuvant QS-21 conjugate vaccine, GM2 and GD2 have been shown to be consistently immunogenic, inducing cytotoxic IgM antibodies in most patients. The immunogenicity of other gangliosides also expressed on melanoma cells such as 9-0-acetyl GD3 and GD3 lactone is currently being tested with this conjugate vaccine approach. From the initiation of our adjuvant vaccine trials in 1975 to the present, the immunogenicity of ganglioside vaccines has increased significantly as vaccine development has progressed. For instance, GM2 antibody responses increased from low titer IgM antibodies induced in occasional patients after whole cell vaccines, to moderate titer IgM antibodies in 86% of patients after GM2/BCG vaccines, to higher titer IgM antibodies in 100% of patients treated with the GM2-KLH plus QS-21 vaccine. These antibodies are capable of mediating complement mediated cytotoxicity of GM2 expressing melanoma cells in the majority of patients and such antibodies, whether naturally produced or vaccine induced, have been associated with a significantly improved disease-free and overall survival. An initial double-blind randomized trial in AJCC Stage III melanoma patients comparing GM2/BCG with BCG alone, demonstrated a 14% improvement in disease-free interval at 4 years and an 11% improvement in overall survival, though neither result achieved statistical significance. Based on these encouraging clinical results and the clearly improved immunogenicity of the GM2-KLH plus QS-21 vaccine compared to the previous GM2/BCG vaccine, the following two large clinical trials are anticipated to begin in 1995-1996. The GM2-KLH plus QS-21 vaccine will be tested in the intergroup setting by ECOG in 450 patients with AJCC Stage II or III melanoma who are free of disease after surgery. Also to be tested in a multicenter trial is a GM2-KLH plus GD2-KLH plus QS-21 vaccine in patients with high risk AJCC Stage II-IV sarcoma after surgical excision of all known disease.
Olivera J. Finn, Keith R. Jerome, Robert A. Henderson, Gabriele Pecher, Nieves Domenech, ,
Published: 1 June 1995
Immunological Reviews, Volume 145, pp 61-89; https://doi.org/10.1111/j.1600-065x.1995.tb00077.x

Abstract:
Many obstacles still stand in the way to eliciting an effective immune response against cancer, even though several antigens and antigenic peptides have been identified as potential tumor targets. All of them, including the MUC-1 mucin, share the caveat of being normal cellular proteins. Unlike all the others, however, MUC-1 expressed on tumors can still be considered a truly tumor-specific antigen. Its expression on normal cells is hidden from the immune system, and its aberrant glycosylation on tumors creates new epitopes recognized by the immune system. Moreover, all other tumor targets identified so far are MHC-restricted peptides that can only be recognized by patients who carry a specific HLA type, or on tumors which continue to express particular HLA alleles. MUC-1 is powerfully different. Recognized as a native molecule independent of MHC, it is a universal immunogen and a universal target, and if made effectively immunogenic, it would be expected to elicit immune responses in all patients, and against numerous MUC-1 expressing human tumors. It may, in fact, be the extraordinary solution to an extraordinary problem of cancer immunity and immunotherapy.
R. Alving Carl, Vladimir Koulchin, , Manuala Rao
Published: 1 June 1995
Immunological Reviews, Volume 145, pp 5-31; https://doi.org/10.1111/j.1600-065x.1995.tb00075.x

Abstract:
In the quest for effective immunization against complex diseases such as cancer, parasitic diseases, AIDS, and other viral infections, numerous peptides and recombinant proteins have been synthesized, examined for the ability to induce antibodies and CTLs, and tested for binding capability and therapeutic or prophylactic efficacy against the original target cell or organism. A liposome formulation, consisting of alum-adsorbed liposomes containing both a potent adjuvant, lipid A, and encapsulated or surface bound antigen, has had a record of safety and strong effectiveness for induction of antibodies in human vaccine trials. These same liposomes can also serve as effective vehicles for delivering conjugated or unconjugated peptides and proteins to antigen presenting cells for presentation via MHC class I and class II pathways for induction of CTLs and antibodies in experimental animal models. Liposomal lipid A appears to be extremely important, and is often a requirement, as an adjuvant for induction of CTLs against liposomal peptide antigens. Computer-generated molecular modelling analysis of small unconjugated or lipid-conjugated peptides strongly suggests that the expression of peptide antigen on the surface of the liposomes can be an important factor both in the induction of antibodies and in determining antibody specificities to small peptides. However, antigenic surface expression of liposomal peptide is not required for induction of CTLs. The data suggest that small synthetic peptides, synthesized with or without a lipid tail, or chemically conjugated to the surface of liposomes, might serve as effective antigenic epitopes, in combination with liposomal lipid A for induction of antibodies and CTLs.
Nicole M. Parish, Patricia R. Hutchings, Lxjrraine O'reilly, Ruby Quartey-Papafio, Don Healey, Pat Ozegbe, Anne Cooke
Published: 1 April 1995
Immunological Reviews, Volume 144, pp 269-300; https://doi.org/10.1111/j.1600-065x.1995.tb00073.x

Abstract:
This chapter aims to describe ways in which autoimmunity can be prevented or reversed and 'self-tolerance' re-established. To this end we have largely restricted our overview to the two main autoimmune disease models with which we are involved, i.e. IDDM in NOD mice and EAT in H-2k mice although, where appropriate and to demonstrate a particular point, other models are mentioned. The chapter has been divided into sections covering protection afforded by 1) transgenes, 2) autoantigen and 3) by reagents targetting T-cell surface molecules. Where established, the mechanism by which protection or tolerance is achieved is described but where, as in most cases, it is unknown the possibilities are discussed. Investigations using T-cell lines and clones and on islet regeneration which are currently being followed as part of a comprehensive approach to the study of autoimmunity are included as separate sections and their relevance discussed.
Tomas Olsson
Published: 1 April 1995
Immunological Reviews, Volume 144, pp 245-268; https://doi.org/10.1111/j.1600-065x.1995.tb00072.x

Abstract:
In EAE/MS, effector molecules are produced as a result of the interaction between T lymphocytes and antigen-presenting cells and the spectrum of cytokines produced is likely to decisively influence the disease outcome. These events may be more important, or at least more easily accessible to therapeutic intervention, than particular autoantigen specificities. Data from EAE suggest that cytokines connected to the Th1 phenotype of lymphocytes, especially IFN-gamma but also TNF-beta, TNF-alpha and IL-12, may promote inflammation while cytokines connected to the Th2 subset, IL-4, IL-10 and TGF-beta, may potentially have a role in disease limitation. It will be important to accurately study cytokines during immunotherapeutic interventions and in relation to immunogenetic variables in order to aim at immunotherapeutically intervening in the Th1, Th2 balance as well as counteracting disease-promoting cytokines such as IFN-gamma and TNF-alpha or promoting the action of downregulatory cytokines such as IL-10 and TGF-beta.
Kyuhei Tomonari, Sue Fairchild, Oliver A. Rosenwasser
Published: 1 February 1993
Immunological Reviews, Volume 131, pp 131-168; https://doi.org/10.1111/j.1600-065x.1993.tb01534.x

Abstract:
In mice, V beta-specific negative selection is mediated by a number of superantigens encoded by various mouse mammary tumor viruses. We have identified Mtv-3, Mtv-27, Mtv-44, Mtv-8, Mtv-9, Mtv-11, and MMTV(D2.GD), and have confirmed Mtv-1. Although specificities of superantigens correlate well with sequences of their carboxy terminal regions, Mtv-44 appears to be an exception: the product is specific for V beta 3, V beta 6, V beta 8.1, and V beta 9. It remains to be determined whether Mtv-44 produces one or two different superantigens to exhibit this specificity. V beta 5+ T-cell deletion is induced by two groups of superantigens: V beta 3-specific superantigens encoded by Mtv-1, Mtv-3, Mtv-6, Mtv-13, Mtv-27, and Mtv-44, and V beta 11-specific superantigens encoded by Mtv-8, Mtv-9, and Mtv-11. Furthermore, these V beta 3-specific superantigens are also specific for V beta 17a(cz). In contrast, V beta-specific positive selection and V alpha-specific positive and negative selection do not seem to involve non-H-2 (super)antigens, although their involvement can not be excluded. In the near future, superantigens, powerful modulators of T-cell functions, will be exploited for clinical applications.
Michael J. Irwin, Keith R. Hudson, Kristina T. Ames, John D. Fraser, Nicholas R. J. Gascoigne
Published: 1 February 1993
Immunological Reviews, Volume 131, pp 61-78; https://doi.org/10.1111/j.1600-065x.1993.tb01530.x

Abstract:
The last few years have seen an enormous jump in our knowledge and understanding of T-cell activation by superantigens. Clearly, a great number of infectious and parasitic organisms utilize superantigens as part of a strategy to evade the immune response of their host. The ability to modulate superantigen effects will give us new means to fight infections, and the knowledge of T-cell activation that we have gained from study of superantigens will, in turn, allow us to modulate the immune system in new ways.
, Josselyne Salaun, Catherine Corbel, Antonio Bandeira, Nicole Le Douarin
Published: 1 June 1993
Immunological Reviews, Volume 133, pp 225-240; https://doi.org/10.1111/j.1600-065x.1993.tb01518.x

Abstract:
From experimental observations on induction of transplantation tolerance, we discuss a model that accounts for tissue-specific tolerance to antigens not expressed inside the thymus. It is postulated that antigens presented to differentiating T cells by thymic epithelium (or at large within the thymic environment) positively select and activate self-reactive T cells. A developmental program and/or prevalent conditions in the thymic environment restrict the proliferative potential and the class of effector functions that can be exerted by differentiating T cells activated in the thymus. These do not mediate inflammatory or cytolytic activities, but instead will produce the appropriate mediators to inhibit aggressive effector activities by other T cells activated in their proximity. Such "regulatory" functions will be locally expressed at the periphery upon recognition of tissue antigens shared with the thymus, towards newly formed thymic emigrants directed at tissue-specific antigens expressed by the same "target" cells. This mechanism imposes "dominant tolerance", based on specific self-recognition and predominantly established in the embryonic and neonatal period. Throughout life, the process of thymic positive selection results in all newly-formed T cells being susceptible to such suppressive mechanisms, but becoming increasingly refractory with time in the resting, post-differentiative stage. Absence of antigen (nonself) in the embryonic and neonatal life therefore allows for the accumulation of such "suppression-resistant" antigen-reactive T cells that will mount aggressive responses upon antigenic exposure. Tolerance or immunity thus represent two classes of specific immune responses, the relative predominance of which is determined by the frequency of each type of effector T cell, representing the antigenic overlap between thymic and peripheral tissues, as well as the frequency of tissue-specific T-cell generation, and the kinetics of peripheral antigenic exposure. Tolerance induced by hemopoietic cells to all other tissues is also "dominant" and based on thymic colonization and persistence of antigenic cells, with the consequent positive selection of regulatory T cells and peripheral conditions for the establishment of suppression. Upon this simple model, that ensures "interclonal class regulation" by "bridging" regulatory and effector T cells through the recognition of different antigens on the same target cell, other mechanisms which are based on V-region interactions among T cells (Ben-Nun et al. 1981, Pereira et al. 1989, Webb & Sprent 1990, Gaur et al. 1993) might well operate to ensure "dominant tolerance" by self-reactivity and class regulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Rolf M. Zinkernagel, Demetrius Moskophidis, Thomas Kündig, Stephan Oehen, Hanspeter Pircher, Hans Hengartner
Published: 1 June 1993
Immunological Reviews, Volume 133, pp 199-223; https://doi.org/10.1111/j.1600-065x.1993.tb01517.x

Scott W. Umlauf, Bart Beverly, Sang-Mo Kang, Kurt Brorson, Annte-Chen Tran, Ronald H. Schwartz
Published: 1 June 1993
Immunological Reviews, Volume 133, pp 177-197; https://doi.org/10.1111/j.1600-065x.1993.tb01516.x

Abstract:
The delivery of costimulation and the effects of the anergic state impinge on IL-2 production via different molecular mechanisms. The strongest experimental support at this stage suggests that CD28 signaling effects mRNA stability of several lymphokine genes including IL-2. While there may also be transcriptional effects of CD28 signals in human cells, controversy surrounding relevant TCR mimics must be addressed. In the case of clonal anergy, however, transcriptional non-responsiveness is evident when anergic cells are restimulated with TCR and costimulatory signals. This repression affects predominantly AP-1 activity. So far, the nature of the repression has not been identified.
, Hiroshi Kosaka, Er-Kai Gao, , Susan R. Webb
Published: 1 June 1993
Immunological Reviews, Volume 133, pp 151-176; https://doi.org/10.1111/j.1600-065x.1993.tb01515.x

Abstract:
Parent-->F1 bone marrow (BM) chimeras provide a useful model for studying self tolerance induction. When prepared with supralethal irradiation (1300 cGy) and conditioned with anti-T cell antibodies, parent-->F1 BM chimeras are devoid of host BM-derived cells; host H-2 expression is apparent in both the intrathymic and extrathymic environments but is limited to non BM-derived cells. When parent-->F1 chimeras are injected with T cells from normal parental strain mice, the expression of host H-2 antigens on nonprofessional APC might be expected to induce tolerance through induction of clonal anergy. In practice, this does not occur. Instead, a small proportion of the injected T cells is induced to proliferate and differentiate into effector cells. Tolerance is not seen. Similarly, tolerance is not apparent when thymectomized parent-->F1 chimeras are given parental strain thymus grafts. These findings suggest that the expression of host H-2 antigens in the post-thymic environment of chimeras is not intrinsically tolerogenic for mature T cells or recent thymic emigrants. Interestingly, post-thymic tolerance does occur when parental strain T cells differentiate in the endogenous thymus of chimeras. Thus, when mature CD8+ cells are prepared from thymus vs lymph nodes (LN) of parent-->F1 chimeras, tolerance to host class I antigens is more marked in LN than thymus; this applies to cytotoxic T lymphocyte (CTL) precursors, generated by limiting dilution analysis. It would appear therefore that many of the host-reactive CTL precursors generated in the thymus of chimeras undergo tolerance induction (deletion or irreversible inactivation) in the post-thymic environment. We suggest that such tolerance is a reflection of a covert form of tolerance induced in the thymus: intrathymic contact with host antigens on thymic epithelial cells (TEC) in chimeras does not delete typical CTL precursors, but these cells are rendered "semi-tolerant". When cultured in vitro in the presence of lymphokines, the cells are able to recover and differentiate into CTL. In vivo, however, the cells recognize antigen in the periphery in the relative absence of lymphokines and the cells die. Although host class I expression on TEC in chimeras deletes only a small proportion of CTL precursors, contact with TEC induces strong tolerance of CD8+ cells in terms of helper-independent proliferative responses in vitro and induction of lethal graft-versus-host disease in vivo. We postulate that these latter responses are controlled by high-affinity T cells, whereas typical CTL generated in LDA are predominantly low-affinity cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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