Decreased T Follicular Regulatory Cell/T Follicular Helper Cell (TFH) in Simian Immunodeficiency Virus-Infected Rhesus Macaques May Contribute to Accumulation of TFH in Chronic Infection

T follicular helper cells (T-FH) are critical for the development and maintenance of germinal center (GC) and humoral immune responses. During chronic HIV/SIV infection, T-FH accumulate, possibly as a result of Ag persistence. The HIV/SIV-associated T-FH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4(+) T cells (T-FR). T-FR are natural regulatory T cells (T-REG) that migrate into the follicle and, similar to T-FH, upregulate CXCR5, Bcl-6, and PD1. In this study, we identified T-FR as CD4(+)CD25(+)FOXP3(+)CXCR5(+)PD1(hi)Bcl-6(+) within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that T-FR exhibit a distinct transcriptional profile with shared features of both T-FH and T-REG, including intermediate expression of FOXP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of T-FR and both T-FH and GC B cells, as well as levels of CD4(+) T cell proliferation. Post SIV infection, the T-FR/T-FH ratio was reduced with no change in the frequency of T-REG or T-FR within the total CD4(+) T cell pool. Finally, we examined whether higher levels of direct virus infection of T-FR were responsible for their relative depletion post SIV infection. We found that T-FH, T-FR, and T-REG sorted from SIV-infected RM harbor comparable levels of cell-associated viral DNA. Our data suggest that T-FR may contribute to the regulation and proliferation of T-FH and GC B cells in vivo and that a decreased T-FR/T-FH ratio in chronic SIV infection may lead to unchecked expansion of both T-FH and GC B cells.