CD154 Blockade Alters Innate Immune Cell Recruitment and Programs Alloreactive CD8+ T Cells into KLRG-1high Short-Lived Effector T Cells
Open Access
- 5 July 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (7), e40559
- https://doi.org/10.1371/journal.pone.0040559
Abstract
CD154/CD40 blockade combined with donor specific transfusion remains one of the most effective therapies in prolonging allograft survival. Despite this, the mechanisms by which these pathways synergize to prevent rejection are not completely understood. Utilizing a BALB/c (H2-Kd) to B6 (H2-Kb) fully allogeneic skin transplant model system, we performed a detailed longitudinal analysis of the kinetics and magnitude of CD8+ T cell expansion and differentiation in the presence of CD154/CD40 pathway blockade. Results demonstrated that treatment with anti-CD154 vs. DST had distinct and opposing effects on activated CD44high CD62Llow CD8+ T cells in skin graft recipients. Specifically, CD154 blockade delayed alloreactive CD8+ T cell responses, while DST accelerated them. DST inhibited the differentiation of alloreactive CD8+ T cells into multi-cytokine producing effectors, while CD40/CD154 blockade led to the diminution of the KLRG-1low long-lived memory precursor population compared with either untreated or DST treated animals. Moreover, only CD154 blockade effectively inhibited CXCL1 expression and neutrophil recruitment into the graft. When combined, anti-CD154 and DST acted synergistically to profoundly diminish the absolute number of IFN-γ producing alloreactive CD8+ T cells, and intra-graft expression of inflammatory chemokines. These findings demonstrate that the previously described ability of anti-CD154 and DST to result in alloreactive T cell deletion involves both delayed kinetics of T cell expansion and differentiation and inhibited development of KLRG-1low memory precursor cells.Keywords
This publication has 32 references indexed in Scilit:
- Nondepleting Anti-CD40-Based Therapy Prolongs Allograft Survival in Nonhuman PrimatesAmerican Journal of Transplantation, 2011
- Selective CD28 Blockade Attenuates Acute and Chronic Rejection of Murine Cardiac Allografts in a CTLA-4-Dependent MannerAmerican Journal of Transplantation, 2011
- Limiting the Amount and Duration of Antigen Exposure during Priming Increases Memory T Cell Requirement for Costimulation during RecallThe Journal of Immunology, 2011
- Alloimmune Activation Enhances Innate Tissue Inflammation/Injury in a Mouse Model of Liver Ischemia/Reperfusion InjuryAmerican Journal of Transplantation, 2010
- CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular InjuryThe American Journal of Pathology, 2008
- Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fatesThe Journal of Experimental Medicine, 2008
- Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-bet Transcription FactorImmunity, 2007
- CD154 Blockade, Sirolimus, and Donor-Specific Transfusion Prevents Renal Allograft Rejection in Cynomolgus Monkeys Despite Homeostatic T-Cell ActivationTransplantation, 2007
- IDEC-131 (Anti-CD154), Sirolimus and Donor-Specific Transfusion Facilitate Operational Tolerance in Non-Human PrimatesAmerican Journal of Transplantation, 2005
- Donor-specific antigen transfusion-mediated skin-graft tolerance results from the peripheral deletion of donor-reactive CD8+ T cellsTransplantation, 2003