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Paucity of interleukin (IL-21)-producing CD4+ T-cells is associated with Th17 cell depletion in SIV-infection of rhesus macaques

Luca Micci, Barbara Cervasi, Zachary S. Ende, Robin I. Iriele, Elane Reyes-Aviles, Carol Vinton, James Else, Guido Silvestri, Aftab A. Ansari, Francois Villinger, Savita Pahwa, Jacob D. Estes, Jason M. Brenchley, Mirko Paiardini

Abstract

Interleukin (IL)-21 regulates Th17 cell homeostasis, enhances the differentiation of memory B cells and antibody-secreting plasma cells, and promotes the maintenance of CD8+ T-cell responses. In this study, we investigated the phenotype, function, and frequency of blood and intestinal IL-21-producing cells in nonhuman primates that are hosts of progressive (rhesus macaques; RMs) and nonprogressive (sooty mangabeys; SMs) SIV infection. We found that, in both species, memory CD4+CD95+CCR6- T-cells are the main IL-21 producers, and that only a small fraction of CD4+IL-21+ T-cells produce IL-17. During chronic SIV infection of RMs, CD4+IL-21+ T-cells were significantly depleted in both blood and rectal mucosa, with the extent of this depletion correlating with the loss of Th17 cells. Furthermore, treatment with IL-21 increased the in vivo levels of Th17 cells in SIV-infected RMs. In contrast, normal levels of CD4+IL-21+ T-cells were found in SIV-infected SMs. Collectively, these data indicate that depletion of IL-21-producing CD4+ T-cells distinguishes progressive from nonprogressive SIV infection of RMs and SMs, and suggest that depletion of CD4+IL-21+ T-cells is involved in the preferential loss of Th17 cells that is associated with SIV disease progression. Further pre-clinical studies of IL-21 as a potential immunotherapeutic agent for HIV infection may be warranted.

  • Submitted April 2, 2012.
  • Accepted August 31, 2012.