Systemic Autoimmunity Remodels Microbiota-Reactive CD4⁺ T Cell Immunity

The gut microbiota contributes to autoimmune disease, yet how systemic autoimmunity reshapes microbiota-reactive CD4⁺ T cell responses and how these cells influence disease progression remain poorly understood. Previous studies have linked microbiota-reactive T cells and lupus-associated pathobionts to disease pathogenesis, but the pathways that regulate the accumulation, differentiation, and pathogenicity of microbiota-reactive T cells during autoimmunity remain unclear. Here, we show that systemic autoimmunity drives the expansion, accumulation, and functional differentiation of microbiota-reactive CD4⁺ T cells. Using segmented filamentous bacteria tetramers, we identify antigen-defined microbiota-reactive CD4⁺ T cells that undergo systemic accumulation and Th1/Tfh polarization during disease. We further identify reactivation of intestinal dendritic cell trafficking as a mechanism linking systemic autoimmunity to the accumulation of microbiota-reactive CD4⁺ T cells in peripheral tissues. In contrast to commensal-reactive T cells, CD4⁺ T cells conditioned by the lupus-associated pathobiont Enterococcus gallinarum markedly exacerbate autoimmunity following adoptive transfer through IL-21- and IFNγ-dependent mechanisms. Together, these findings demonstrate that systemic autoimmunity reshapes microbiota-reactive CD4⁺ T cell immunity and establish microbial context as a critical determinant of microbiota-reactive CD4⁺ T cell pathogenicity.