Maintenance of Intestinal Th17 Cells and Reduced Microbial Translocation in SIV-infected Rhesus Macaques Treated with Interleukin (IL)-21
Open Access
- 4 July 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 9 (7), e1003471
- https://doi.org/10.1371/journal.ppat.1003471
Abstract
In pathogenic HIV and SIV infections of humans and rhesus macaques (RMs), preferential depletion of CD4+ Th17 cells correlates with mucosal immune dysfunction and disease progression. Interleukin (IL)-21 promotes differentiation of Th17 cells, long-term maintenance of functional CD8+ T cells, and differentiation of memory B cells and antibody-secreting plasma cells. We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections. To test this hypothesis, we infected 12 RMs with SIVmac239 and at day 14 post-infection treated six of them with rhesus rIL-21-IgFc. IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation. Compared to untreated animals, IL-21-treated RMs showed (i) higher expression of perforin and granzyme B in total and SIV-specific CD8+ T cells and (ii) higher levels of intestinal Th17 cells. Remarkably, increased levels of Th17 cells were associated with reduced levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation in the chronic infection. In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells. Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy. In the gastrointestinal tract, preferential depletion of CD4+ Th17 cells occurs during the early stage of pathogenic HIV/SIV infections and correlates with loss of mucosal integrity, microbial translocation, immune activation and disease progression. As such, therapeutic intervention aimed at preserving intestinal Th17 cells may be of critical importance. IL-21 plays an important role in promoting the differentiation and survival of Th17 cells, as well as in stimulating CD8+ T cell cytolytic function. Here, we treated SIV-infected rhesus macaques with IL-21-IgFc in the early stage of infection. Consistent with the main functions of IL-21, we found that IL-21 treated animals had higher expression of perforin and granzyme B in total and SIV-specific CD8+ T cells and higher frequencies of intestinal Th17 cells as compared to untreated controls. Remarkably, the increased proportions of Th17 cells during early infection was associated with significantly lower levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation during chronic infection. Thus, our results suggest that IL-21 treatment in SIV-infected RMs is effective in preserving intestinal Th17 cells and results in an improvement of mucosal immune function. Further preclinical studies may be warranted to test IL-21 during chronic infection and in conjunction with antiretroviral therapy.Keywords
This publication has 73 references indexed in Scilit:
- Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infectionMucosal Immunology, 2012
- Interleukin-21 administration to rhesus macaques chronically infected with simian immunodeficiency virus increases cytotoxic effector molecules in T cells and NK cells and enhances B cell function without increasing immune activation or viral replicationVaccine, 2011
- Simian immunodeficiency virus infection in rhesus macaques induces selective tissue specific B cell defects in double positive CD21+CD27+ memory B cellsClinical Immunology, 2011
- Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expressionNature Medicine, 2011
- Critical role for IL-21 in both primary and memory anti-viral CD8+ T-cell responsesEuropean Journal of Immunology, 2010
- Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaquesMucosal Immunology, 2008
- The Biological Functions of T Helper 17 Cell Effector Cytokines in InflammationImmunity, 2008
- IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinomaCancer Immunology, Immunotherapy, 2008
- TH-17 cells in the circle of immunity and autoimmunityNature Immunology, 2007
- Microbial translocation is a cause of systemic immune activation in chronic HIV infectionNature Medicine, 2006