Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection

摘要

T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4⁺ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4⁺CD25⁺FoxP3⁺CXCR5⁺PD1^hiBcl-6⁺ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, 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 TFR and both TFH and GC B-cells as well as levels of CD4⁺ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG 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 suggests 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.