Regulation and function of immune suppressive T cells in aging

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ABSTRACT Several recent studies uncovered that active immune suppressive mechanisms develop progressively in aging and dampen immune function. Importantly, these data also demonstrate that the aged immune system is amenable to restoration, if these mechanisms are controlled. Our new data demonstrated that a novel population of immune suppressive CD4+ T cells that produce high levels of IL-10 accumulates with age in both mice and humans. These cells are required for maintaining the high levels of systemic IL-10 present in aged mice. Importantly, blockade of IL-10 signaling in aged mice restores their vaccine-driven germinal center B cell responses similar to levels observed in young mice. Flow cytometric and single cell genomics analyses show that the majority of these IL-10-producing CD4+ T cells bear markers of T follicular helper (Tfh) cells, a cell type critical for antibody production, and thus, we refer them as Tfh10 cells. Tfh10 express several Tfh-specific genes, but they cluster distinctly from canonical Tfh and also express several Th1 transcripts, in addition to IL-10, suggesting an altered T cell differentiation state. Importantly, we also found that antigen-specific Tfh10 cells emerge as early as day 8 after vaccination in aged mice, but not in young mice. Our data also link these cells with “inflammaging” as IL-6 and Il-21 are independently required for the accumulation of Tfh10 cells in aged mice. Together, our preliminary data drive our overall hypothesis that IL-6 and IL-21 promote the development and survival, respectively, of IL-10-producing Tfh cells, and IL-10 signaling to B cells is critical to limit durable vaccine responses. These hypotheses will be tested in 3 aims. In Sp.Aim1, we will determine the mechanism(s) that control the development and accumulation of Tfh10 cells with age. Using flow cytometry and sc genomics to analyze the antigen-specific response to vaccination, we will test the following hypotheses: (i) Tfh10 cells arise from an altered differentiation process early after vaccination that requires IL-6; (ii) IL-21, but not IL-6, promotes the long-term survival of Tfh10 cells by antagonizing Bim. In Sp.Aim2, we will identify the cellular loci of action and function of IL-10 on vaccine-driven protective immunity in aging, with the following hypotheses: (i) direct IL- 10 signaling to B cells limits their response to vaccination (ii) excessive IL-10 suppresses generation of long- lived plasma cells (PCs); and (iii) aged Tfh10 cells are required to limit vaccine-induced B cell responses in young mice. In Sp.Aim3, we will determine the role of IL-10 in controlling influenza vaccine responsiveness in aged non- human primates, by administering a validated Rhesus macaque IL-10R-Fc (or control Ig) at the time of a standard influenza vaccination and (i) analyzing vaccine-elicited immune responses, as well as local and systemic inflammation; and (ii) correlating these responses with resistance to a subsequent Flu challenge. Overall, this research is highly significant and innovative because it tackles two important aspects of the immunology of aging, by providing in-depth analyses, at the cellular and molecular level, of the mechanisms driving the intricate relationship between “inflammaging” and immune suppression. In addition, it can have important potential translational implications, as we will test the efficacy of transient blockade of IL-10 signaling on vaccine responsiveness in aged Rhesus macaques.