Associations of Simian Immunodeficiency Virus (SIV)-Specific Follicular CD8+ T Cells with Other Follicular T Cells Suggest Complex Contributions to SIV Viremia Control

Abstract

Follicular CD8 T (fCD8) cells reside within B cell follicles and are thought to be immune-privileged sites of HIV/SIV infection. We have observed comparable levels of fCD8 cells between chronically SIV-infected rhesus macaques with low viral loads (LVL) and high viral loads (HVL), raising the question concerning their contribution to viremia control. In this study, we sought to clarify the role of SIV-specific fCD8 cells in lymph nodes during the course of SIV infection in rhesus macaques. We observed that fCD8 cells, T follicular helper (Tfh) cells, and T follicular regulatory cells (Tfreg) were all elevated in chronic SIV infection. fCD8 cells of LVL animals tended to express more Gag-specific granzyme B and exhibited significantly greater killing than did HVL animals, and their cell frequencies were negatively correlated with viremia, suggesting a role in viremia control. Env- and Gag-specific IL-21 Tfh of LVL but not HVL macaques negatively correlated with viral load, suggesting better provision of T cell help to fCD8 cells. Tfreg positively correlated with fCD8 cells in LVL animals and negatively correlated with viremia, suggesting a potential benefit of Tfreg via suppression of chronic inflammation. In contrast, in HVL macaques, Tfreg and fCD8 cell frequencies tended to be negatively correlated, and a positive correlation was seen between Tfreg number and viremia, suggesting possible dysfunction and suppression of an effective fCD8 cell immune response. Our data suggest that control of virus-infected cells in B cell follicles not only depends on fCD8 cell cytotoxicity but also on complex fCD8 cell associations with Tfh cells and Tfreg.

Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8 + T cells

“…B cell follicles are thought to represent immunoprivileged sites that potentiate HIV persistence as a consequence of limited immunosurveillance by CD8 + T cells (2,(28)(29)(30)(31). Previous studies have also demonstrated an inverse correlation between the frequency of follicle-homing (CXCR5 + ) CD8 + T cells and pVL (18,32,33). In line with these findings and the relative absence of vRNA + cells in the B cell follicles of ECs (Fig.…”

Early T Follicular Helper Cell Responses and Germinal Center Reactions Are Associated with Viremia Control in Immunized Rhesus Macaques

“…10B and C) emphasizes the pivotal role of the systemic boost immunization in the development of protective SIV humoral immunity. Other factors of course may impact viremia levels, such as virus-specific cytotoxic T lymphocytes and their interactions with other T cell subsets (41,84,85) and availability of virussusceptible T helper cell subsets such as Th17 or CCR6 expressing CD4 ϩ T cells (86)(87)(88)(89). Nevertheless, the strong association between acute-phase viremia control and the early GC SIV ESM B cell response at day 3 postboost, a time point not previously associated with generation of antigen-specific responses within GCs, illustrates that following immunization, early T FH -dependent SIV specific memory B cell responses generated in GCs are important for control of viral replication.…”

Follicular T-cell subsets in HIV infection

“…This was first described in the 1980s [11], although their specificity and function was not known. Virus-specific cytotoxic CD8+ T cells were shown subsequently to be present at significantly lower concentrations within the B cell follicle as compared to extrafollicular tissues in both HIV and SIV infection [2,12,14,26,27], and this has been confirmed in more recent studies [28][29][30][31]. fCD8 share the CXCR5 + CCR7-phenotype with GC Tfh and GC Tfr, which is required for their localization into the GC, and their differentiation may be partially dependent on Bcl6 [27].…”