CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease

Abstract

CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored. In this study, we show that CD8 T cells acquire a CD4 Tfh profile in the absence of functional regulatory T cells in both the IL-2-deficient and scurfy mouse models. Depletion of CD8 T cells mitigates autoimmune pathogenesis in IL-2-deficient mice. CD8 T cells express the B cell follicle-localizing chemokine receptor CXCR5, a principal Tfh transcription factor Bcl6, and the Tfh effector cytokine IL-21. CD8 T cells localize to the B cell follicle, express B cell costimulatory proteins, and promote B cell differentiation and Ab isotype class switching. These data reveal a novel contribution of autoreactive CD8 T cells to autoimmune disease, in part, through CD4 follicular-like differentiation and functionality.

Roles of T Follicular Helper Cells and T Follicular Regulatory Cells in Autoantibody Production in IL-2–Deficient Mice

“…To analyze the role of Tfh and Tfr cells in the IL-2 KO, we obtained IL-2 KO mice on the C57BL/6 (B6) background because this strain was genetically compatible with most conditional KO strains that are also on the B6 background. We found that IL-2 KO mice on the B6 background in our facility were healthier than reported for IL-2 KO mice on the BALB/c background (38,39,43). In our colony, most B6 IL-2 KO mice live longer than 5 wk and have a lifespan more similar to what was seen with IL-2 KO mice on the mixed 129-O1a 3 C57BL/6 background (37,38).…”

“…Autoantibodies specific for colon cells were detected in these mixed background IL-2 KO mice (37). In BALB/c IL-2 KO mice, high levels of autoantibodies to RBCs lead to severe AIHA and much earlier death than on a mixed background (38,39). In BALB/c IL-2 KO mice, conventional CD4 + Tfh cells are elevated as well as an unusual CD8 + Tfh-like population with B cell helper activity (39).…”

“…In BALB/c IL-2 KO mice, high levels of autoantibodies to RBCs lead to severe AIHA and much earlier death than on a mixed background (38,39). In BALB/c IL-2 KO mice, conventional CD4 + Tfh cells are elevated as well as an unusual CD8 + Tfh-like population with B cell helper activity (39). Both CD4 + and CD8 + cells contribute to autoantibody production and autoimmune disease in the BALB/c IL-2 KO model (39).…”

“…On a mixed 129/ 01a 3 C57BL/6 genetic background, IL-2 KO mice die early (at 9 wk on average) and almost invariably develop severe colitis (37,38). IL-2 KO mice on the BALB/c background die between 3 and 5 wk from AIHA caused by the production of autoantibodies to RBCs (38,39). In these mice, Tfh cells increased in number because IL-2 suppresses Tfh cell differentiation by inhibiting Bcl6 transcription (40)(41)(42).…”

Compromised steady‐state germinal center activity with age in nonhuman primates

“…areas represent immunologically privileged areas with limited presence of potential CTLs(Connick et al, 2007). Besides their cytolytic activity, fCD8 cells can promote isotype switching of B cells in the settings of autoimmunity(Valentine et al, 2018) while IL-6, a positive regulator of Tfh cells(Eto et al, 2011), can also induce IL21-producing CD8 T cells with follicular helper function(Yang et al, 2016) and therefore further induce humoral responses indirectly through local IL21 production. Despite a trend for higher baseline CD3 hi CD4 lo T cells in old compared to young LNs, a significant positive correlation between Tfh and CD3 hi CD4 lo was found only in young animals, indicating a possible "helper" fCD8 T-cell function in young NHPs.Tissue inflammation and immune activation may play a significant role in follicular immunodynamics(Ferrando-Martinez et al, 2018).…”