Maintenance of Intestinal Th17 Cells and Reduced Microbial Translocation in SIV-infected Rhesus Macaques Treated with Interleukin (IL)-21

PLoS Pathogens

Francois Villinger¹  Jacob D. Estes²  Kirk Easley³  Colleen S. McGary⁴  Kenneth A. Rogers⁴  Zachary S. Ende⁴  Barbara Cervasi⁴  Savita Pahwa⁴  Benton Lawson⁴  Robin I. Iriele⁴  Luca Micci⁴  James G. Else⁴  Guido Silvestri⁴  Mirko Paiardini⁵  Suresh Pallikkuth⁵ 

[1] AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, SAIC-Frederick, Frederick, Maryland, United States of America;Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Atlanta, Georgia, United States of America;Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America;Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America;University of Miami Miller School of Medicine, Miami, Florida, United States of America

关键词: T cells;    Gastrointestinal tract;    Cytotoxic T cells;    Cloning;    Blood plasma;    Immune activation;    Memory B cells;    SIV;   

DOI  :  10.1371/journal.ppat.1003471

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY