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

• Published in: Blood 2012-11, Vol.120 (19), p.3925-3935
• Main Authors: Micci, Luca, Cervasi, Barbara, Ende, Zachary S., Iriele, Robin I., Reyes-Aviles, Elane, Vinton, Carol, Else, James, Silvestri, Guido, Ansari, Aftab A., Villinger, Francois, Pahwa, Savita, Estes, Jacob D., Brenchley, Jason M., Paiardini, Mirko
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Hematologic and hematopoietic diseases; Homeostasis - immunology; Human immunodeficiency virus; Immunobiology; Immunophenotyping; Interleukins - biosynthesis; Intestinal Mucosa - metabolism; Intestines - immunology; Lymphocyte Activation - immunology; Lymphocyte Depletion; Macaca mulatta; Medical sciences; Phenotype; Primates; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - metabolism; Simian immunodeficiency virus; Spleen - cytology; Spleen - immunology; Th17 Cells - immunology; Th17 Cells - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-04-420240

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 preclinical studies of IL-21 as a potential immunotherapeutic agent for HIV infection may be warranted.