Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Abstract

Chronic HIV infection is associated with accumulation of germinal center T follicular helper cells (GC-Tfh) in the lymphoid tissue. The GC-Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC-Tfh cells in the lymphoid tissue and its association with viral persistence and antibody production during chronic SIV/HIV infection is not known. To address this, here we characterized the expression of CXCR3, CCR4, and CCR6 on GC-Tfh in lymph nodes following SIVmac251 infection in rhesus macaques (RMs). In SIV naïve RM, only a small fraction of GC-Tfh expressed CXCR3, CCR4 and CCR6. However, during chronic SIV infection, the majority of GC-Tfh cells expressed CXCR3, while the proportion of CCR4+ cells did not change and CCR6+ cells decreased. CXCR3+ but not CXCR3− GC-Tfh produced IFN-γ (Th1 cytokine) and IL-21 (Tfh cytokine) while both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4+ IFN-γ+ T cells within the hyperplastic follicles during chronic SIV infection. CXCR3+ GC-Tfh also expressed higher levels of ICOS, CCR5 and α4β7, contained more copies of SIV DNA compared to CXCR3− GC-Tfh cells. However, both CXCR3+ and CXCR3− GC-Tfh delivered help to B cells in vitro for production of IgG. 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 hypergammaglobulinemia and viral reservoirs.

Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection

“…Recently, others and we reported an aberrant accumulation of virus-infected Tfh cells in the lymph nodes (LNs) and rectal mucosa of SIV-infected RMs with high viral load (VL) (14,15,(24)(25)(26)(27), which was not evident in vaccinated SIV-infected RMs with low VL during a pathogenic SIVmac251 infection (15). In the current study, we sought to understand the role of antiviral CD8 T cells in limiting the virus-infected Tfh cells.…”

Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells

“…For example, many studies have demonstrated that T H 1 cells maintain flexibility with the T FH cell type (19, 30, 48). More recently, there have also been reports of T H 1-biased T FH cell populations (49, 50). Corroborating these studies, our laboratory has previously demonstrated that T H 1 cells are capable of upregulating a Bcl-6-dependent T FH -like cell state in response to altered IL-2 signaling (28, 30).…”

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

“…In contrast, following immunization with influenza vaccines (19) or HPV vaccines (20) (i.e., during more limited antigen exposure), humoral immune responses were correlated with CXCR3 + CXCR5 + PD-1 + CD4 + T cells, and CXCR3 + CXCR5 + CD4 + T cells were also observed in blood and lymph nodes in rhesus macaques immunized with an SIV vaccine (21). In addition, recent studies in non-human primate models also reported induction of CXCR3 + Tfh in chronic SIV infection (22). Therefore, the contribution of pTfh subsets to the development of protective Ab responses seems to be context dependent and requires further investigation.…”