Function of follicular helper 17 T cells in driving B cells for anti-DNA autoantibody production in patients with SLE

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BACKGROUND: Follicular helper T (TFH) cells play a crucial role in the dysregulated antibody responses in SLE. Circulating TFH17 (cTFH17) subsets are elevated in active lupus, and their frequency is associated with increased disease activity and autoantibody levels, indicating their potential role in disease development by promoting B-cell and autoantibody production. However, how activated cTFH17 cells drive B cell dysregulation for autoantibody production in SLE remains incompletely understood. OBJECTIVE: To investigate the phenotypic function of interleukin (IL)-17A-producing cTFH cells in subjects with SLE, explore their association with clinical parameters and inflammatory markers and demonstrate potential contributions to B cell-mediated autoantibody production METHODS: Forty subjects with SLE were enrolled to characterise and phenotype cTFH or circulating peripheral helper T cell subsets, based on molecule surface expression and intracellular cytokine production by flow cytometry. The correlations of cTFH17 or cTFH17.1 cells with disease activity, anti-double-stranded DNA (dsDNA) autoantibodies and inflammatory cytokines were analysed. The interactions of cTFH17 cells with autoreactive B cell responses were studied in co-culture assays. The proliferation and inducible T cell costimulator (ICOS) upregulation were detected in cTFH17 cells, while autoantibody-secreting cell differentiation and autoantibody production were detected in B cells. RESULTS: The frequencies of cTFH17 and cTFH17.1 cells were significantly elevated in subjects with SLE compared with healthy controls, particularly in those with active disease. These cells exhibited increased activation, as indicated by the expression of ICOS and CD40L. The frequency of activated cTFH17 or cTFH17.1 cells correlated positively with SLE disease activity index 2000 (SLEDAI-2K) scores but not with anti-dsDNA antibody levels. Profiling of inflammatory cytokines revealed the elevated levels of IL-6, IL-8 and IL-17A in individuals with SLE. However, the increased levels of these cytokines did not correlate with the frequency of cTFH17 cells nor SLEDAI-2K scores. In cTFH17-B cell co-cultures, proliferation and activation of cTFH17 cells were detected. There, B cells differentiated into antibody-secreting cells, which secreted anti-DNA autoantibodies. CONCLUSION: cTFH17 cells were significantly expanded and activated in subjects with active SLE, showing a positive correlation with clinical activity. Functionally, cTFH17-B cell interactions enhanced plasma cell generation and autoantibody production. These findings suggest that cTFH17 cells play a key role in SLE pathogenesis.

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