Loss of IL-17–Producing CD8 T Cells during Late Chronic Stage of Pathogenic Simian Immunodeficiency Virus Infection

Abstract

Progressive disease caused by pathogenic SIV/HIV infections is marked by systemic hyperimmune activation, immune dysregulation, and profound depletion of CD4+ T cells in lymphoid and gastrointestinal mucosal tissues. IL-17 is important for protective immunity against extracellular bacterial infections at mucosa and for maintenance of mucosal barrier. Although IL-17–secreting CD4 (Th17) and CD8 (Tc17) T cells have been reported, very little is known about the latter subset for any infectious disease. In this study, we characterized the anatomical distribution, phenotype, and functional quality of Tc17 and Th17 cells in healthy (SIV−) and SIV+ rhesus macaques. In healthy macaques, Tc17 and Th17 cells were present in all lymphoid and gastrointestinal tissues studied with predominance in small intestine. About 50% of these cells coexpressed TNF-α and IL-2. Notably, ∼50% of Tc17 cells also expressed the co-inhibitory molecule CTLA-4, and only a minority (<20%) expressed granzyme B suggesting that these cells possess more of a regulatory than cytotoxic phenotype. After SIV infection, unlike Th17 cells, Tc17 cells were not depleted during the acute phase of infection. However, the frequency of Tc17 cells in SIV-infected macaques with AIDS was lower compared with that in healthy macaques demonstrating the loss of these cells during end-stage disease. Antiretroviral therapy partially restored the frequency of Tc17 and Th17 cells in the colorectal mucosa. Depletion of Tc17 cells was not observed in colorectal mucosa of chronically infected SIV+ sooty mangabeys. In conclusion, our results suggest a role for Tc17 cells in regulating disease progression during pathogenic SIV infection.

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…First and foremost, it is possible that a different "quality" of CD4 ϩ T-cell depletion in natural versus nonnatural SIV hosts at the intestinal mucosal level plays a major role. Indeed, both SIV-infected RM and HIV-infected persons experience a significant and preferential reduction of the IL-17-producing CD4 ϩ (Th17) and CD8 ϩ (Tc17) T-cell subsets throughout the gastrointestinal tract (81)(82)(83)(84). Similarly, the depletion of IL-17-producing innate lymphocytes in the GI tracts of SIV-infected Asian macaques has been demonstrated (85,86).…”

Immunovirological parameters and cytokines in HIV infection

“…Thus, an increase in the secretion of pro-inflammatory cytokines occurs which facilitates the mucosal tissue damage 100,101 , alterations in bacterial flora and the microbial translocation of gut lumen to peripheral blood 102 . In this manner, the increase of immune activation and general inflammation are induced 102,103 and, consequently, the disease progression 104 .…”

Mucosal Th17 Cell Function Is Altered during HIV Infection and Is an Independent Predictor of Systemic Immune Activation

“…Although CD8 + T cells were also documented to produce IL17a (called Tc17 cells) (35,36), a subset analysis including one HIV-uninfected control and one ART-treated individual demonstrated that sigmoid colonic CD4 T cells produced an abundance of IL-17a compared with CD8 T cells (median, CD4: 1.17%; CD8: 0.15%).…”