@article{bacd819af2854191a5659bcbd746ca58,
title = "Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa",
abstract = "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 contribute to immunoregulation. Here, we show that Btla inhibits activation of genes regulating metabolism and cytokine signaling, including Il6 and Hif1a, indicating a regulatory role in humoral immunity. Within mucosal Peyer's patches, we find T-cell-expressed Btla-regulated Tfh cells, while Btla in T or B cells regulates GC B cell numbers. Treg-expressed Btla is required for cell-intrinsic Treg homeostasis that subsequently controls GC B cells. Loss of Btla in lymphocytes results 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.",
keywords = "B cell, CP: Immunology, CP: Microbiology, IgA, Tfh, Tfr, Treg, autoimmunity, germinal center, inhibitory receptor, microbiome",
author = "Caroline Stienne and Richard Virgen-Slane and Lisa Elm{\'e}n and Marisol Veny and Sarah Huang and Jennifer Nguyen and Elizabeth Chappell and Balmert, {Mary Olivia} and Shui, {Jr Wen} and Hurchla, {Michelle A.} and Mitchell Kronenberg and Peterson, {Scott N.} and Murphy, {Kenneth M.} and Ware, {Carl F.} and {\v S}ed{\'y}, {John R.}",
note = "Funding Information: We thank Yoav Altman and Amy Cortez (flow cytometry); Guillermina Garcia (histology); snd Buddy Charbono, Brian Temple, and Diana Sandoval (animal shared resources facilities) at Sanford Burnham Prebys Medical Discovery Institute; and Cheryl Kim and Semra Sehic (flow cytometry facility) at the La Jolla Institute for Immunology. This study was supported by a gift from the Jean Perkins Foundation (C.S.); a fellowship from the Crohn's and Colitis Foundation (J.-W.S.); grants from the Howard Hughes Medical Institute (K.M.M.) and the National Institutes of Health ( P01 DK46763 and U01 AI125955 , M.K.; PO1 AI31238 and P50 HL54619 , K.M.M.; R01 AI067890 , R01 CA164679 , and P01 CA177322 , C.F.W.; and fellowships from the National Institutes of Health ( T32 CA009547 and U01 AI095542 , J.R.{\v S}.), and the American Heart Association ( AHA-14BGIA20380277 , J.R.{\v S}.). We thank Parham Ramezani-Rad for critical review of the manuscript. Funding Information: We thank Yoav Altman and Amy Cortez (flow cytometry); Guillermina Garcia (histology); snd Buddy Charbono, Brian Temple, and Diana Sandoval (animal shared resources facilities) at Sanford Burnham Prebys Medical Discovery Institute; and Cheryl Kim and Semra Sehic (flow cytometry facility) at the La Jolla Institute for Immunology. This study was supported by a gift from the Jean Perkins Foundation (C.S.); a fellowship from the Crohn's and Colitis Foundation (J.-W.S.); grants from the Howard Hughes Medical Institute (K.M.M.) and the National Institutes of Health (P01 DK46763 and U01 AI125955, M.K.; PO1 AI31238 and P50 HL54619, K.M.M.; R01 AI067890, R01 CA164679, and P01 CA177322, C.F.W.; and fellowships from the National Institutes of Health (T32 CA009547 and U01 AI095542, J.R.{\v S}.), and the American Heart Association (AHA-14BGIA20380277, J.R.{\v S}.). We thank Parham Ramezani-Rad for critical review of the manuscript. C.S. designed and performed the experiments and wrote the manuscript. R.V.-S. analyzed the RNA sequencing (RNA-seq) and NanoString data. L.E. and S.N.P. analyzed microbial sequence data and wrote the manuscript. M.V. S.H. J.N. E.C. M.O.B. and M.A.H. performed the experiments. J.-W.S. and M.K. developed the Btlaflox and Tnfrsf14flox genetic animal models. K.M.M. designed experiments and provided financial support and resources for the studies. C.F.W. designed experiments, wrote the manuscript, and provided financial support and resources for the studies. J.R.{\v S}. designed and performed the experiments, wrote the manuscript, and provided financial support for the studies. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = mar,
day = "22",
doi = "10.1016/j.celrep.2022.110553",
language = "English",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
number = "12",
}