Polymorphisms in human HLA class II alleles are associated with elevated susceptibility to many autoimmune diseases, highlighting a critical role for CD4+ T helper cells in driving pathogenesis. Despite multi-layered tolerance mechanisms, the immune repertoire of healthy mice and humans harbors self-reactive CD4+ conventional T cells capable of inducing autoimmunity when not properly regulated. However, little is known about the nature of these endogenous self-reactive CD4+ T cells, with respect to their antigen specificity, differentiation, and functional properties at steady state and in inflammatory settings. Using a clonal approach involving deep T cell receptor (TCR) sequencing paired with the analysis of monoclonal T cell populations from TCR "retrogenic" mice, we identified numerous CD4+ T cell clones that are recurrently enriched in non-lymphoid organs following sustained ablation of regulatory T (Treg) cells. These clones exhibit overt reactivity to splenic dendritic cells and are highly proliferative in the spleen and regional lymph nodes, suggestive of reactivity to widespread self-antigens, yet are not removed from the repertoire via clonal deletion. Phenotypically, these cells exhibit a T follicular helper (Tfh)-like phenotype characterized by expression of Bcl6 and PD-1, and variable expression of the canonical Tfh receptors CXCR5 and ICOS. Functionally, these cells localize as clusters within primary B cell follicles in the splenic white pulp, but do not appear to promote B cell activation. In sum, our work identifies a unique population of broadly self-reactive CD4+ T cells that populate the endogenous repertoire of healthy mice.




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