Accumulation of Th1 biased Tfh in lymphoid tissues during chronic SIV infection defines functionally distinct germinal center Tfh cells

Abstract

Abstract Follicular helper CD4T cells (Tfh) play a critical role in determining the magnitude and quality of antibody (Ab) responses. Chronic HIV infection is associated with hypergammaglobulinemia and germinal center Tfh (GC-Tfh) in lymphoid tissue may contribute to this process. However, the heterogeneous nature of GC-Tfh cells and the relative contribution of specific GC-Tfh subsets to viral persistence and Ab production is not understood in HIV/SIV infections. Here, we characterized the phenotype and function of GC-Tfh cells based on the expression of chemokine receptors associated with Th1 (CXCR3), Th2 (CCR4) and Th17 (CCR6) in lymph nodes following SIV251 infection in rhesus macaques (RMs). In SIV naïve RM, only a small fraction of GC-Tfh expressed CXCR3, CCR4 and CCR6. During chronic SIV infection, despite a global depletion of CD4 T cells, there was an increase in total GC-Tfh cells. Interestingly the majority of expanded GC-Tfh cells expressed CXCR3, while the proportion of CCR4+ cells did not change but CCR6+ cells decreased. CXCR3+ but not CXCR3−GC-Tfh produced IFN-g and IL-21 while both expressed CD40L following stimulation. IHC analysis demonstrated an accumulation of IFN-g+ T cells within the follicles during chronic infection. CXCR3+GC-Tfh also expressed higher levels of ICOS, CCR5 and a4b7, contained more copies of SIV DNA compared to CXCR3−GC-Tfh cells. Both CXCR3+ and CXCR3−GC-Tfh delivered help to B cells in vitro, but CXCR3+ GC-Tfh favored the production of IgG and IgG1. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC-Tfh cells, which are phenotypically and functionally distinct from conventional GC-Tfh cells and contribute to IgG1 biased hypergammaglobulinemia and viral reservoirs