Tlr7-biallelism defines a hyperfunctional state of female B lymphocytes

Enhanced dosage of the Toll-like receptor TLR7 is closely associated with sex disparities in systemic autoimmunity1-3. Remarkably, TLR7 escapes X chromosome inactivation in immune cells of women, leading to elevated protein levels4,5. However, the direct contribution of this process to immune cell function and systemic autoimmunity is unknown. Here, we use novel female Tlr7-reporter mice and identify a unique subset of mature B cells with bi-allelic Tlr7 expression (BiA7), with higher levels of TLR7 protein, poised for immediate differentiation into antibody secreting cells. We show that the epigenomic signature of BiA7 B cells resembles that of memory B cells, and that their development is independent of BCR self-reactivity or MyD88-signaling but is considerably boosted by type I IFN. Such BiA7 B cells accumulate in age-associated atypical memory B cell populations, which contribute to systemic autoimmunity. Accordingly, constitutive ablation of these cells protects mice from lupus development. Thus, Tlr7 expression from the inactive X chromosome characterizes a unique female-specific hyperactive subset of B lymphocytes and underlies systemic autoimmunity. Collectively, this study provides a mechanism to explain the X-linked genetic disparity in B cell immunity and supports future efforts to target X chromosome inactivation maintenance as a broad therapeutic strategy in sex-biased autoimmune disorders.