Btla Signaling in Conventional and Regulatory Lymphocytes Coordinately Tempers Humoral Immunity in the Intestinal Mucosa

The Btla inhibitory receptor limits innate and adaptive immune responses, both preventing the development of autoimmune disease and restraining anti-viral and anti-tumor responses. It remains unclear how the functions of Btla in diverse lymphocytes contributes to immunoregulation. Here, we show that Btla inhibits activation of genes regulating proliferation and cytokine signaling including the transcription factor Myc, indicating a regulatory role in humoral immunity. Within mucosal Peyer’s Patches, we found T cell-expressed Btla regulated Tfh, while Btla in T or B cells regulated GC B cell numbers. Treg-expressed Btla was required for cell-intrinsic Treg homeostasis, that subsequently controlled GC B cells. Loss of Btla in lymphocytes resulted in increased IgA bound to intestinal bacteria, correlating with altered microbial homeostasis and elevations in commensal and pathogenic bacteria. Together our studies provide important insights into how Btla functions as a checkpoint in diverse conventional and regulatory lymphocyte subsets to influence systemic immune responses.