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SerpinB1 regulates homeostatic expansion of IL‐17+ γδ and CD4+ Th17 cells

SerpinB1 is an endogenous inhibitor of serine proteases recognized for its anti‐inflammatory and host‐protective properties. Although loss of serpinB1 in mice does not result in gross immune deregulation, serpinb1a−/− mice display increased mortality and inflammation‐associated morbidity upon challenge with influenza virus. Here, we show that IL‐17A+ γδ and CD4+ Th17 cells are already expanded in the lungs of serpinb1a−/− mice at steady‐state. Both γδ and αβ+ CD4+ CCR6+ T cells isolated from the lungs of naive serpinb1a−/− mice displayed a skewed transcriptional profile relative to WT cells, including increased Th17 signature transcripts [Il17a, l17f, and Rorc (RORγt)] and decreased Th1 signature transcripts [Ifng, Cxcr3, and Tbx21 (T‐bet)] in γδ T cells. In addition to the lung, IL‐17A+ γδ and CD4+ Th17 cells were increased in the spleen of naive serpinb1a−/− mice, despite normal αβ and γδ T cell development in the thymus. Within the γδ T cell compartment, loss of serpinb1a prompted selective expansion of Vγ4+ and Vγ6/Vδ1+ cells, which also displayed elevated expression of the proliferating cell nuclear antigen, Ki‐67, and IL‐17A. Given that serpinb1a is preferentially expressed in WT IL‐17A+ γδ and CD4+ Th17 cell subsets vis‐à‐vis other T cell lineages, our findings reveal a novel function of serpinB1 in limiting untoward expansion of lymphocytes with a Th17 phenotype.