2. Academic Validation
  3. Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa

Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa

  • Cell Rep. 2022 Mar 22;38(12):110553. doi: 10.1016/j.celrep.2022.110553.
Caroline Stienne 1,  Richard Virgen-Slane 1,  Lisa Elmén 2,  Marisol Veny 1,  Sarah Huang 1,  Jennifer Nguyen 1,  Elizabeth Chappell 1,  Mary Olivia Balmert 1,  Jr-Wen Shui 3,  Michelle A Hurchla 4,  Mitchell Kronenberg 3,  Scott N Peterson 2,  Kenneth M Murphy 4,  Carl F Ware 5,  John R Šedý 6
Affiliations

Affiliations

  • 1 Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 2 Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 3 La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  • 4 Department of Pathology and Immunology, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63110, USA.
  • 5 Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: cware@sbpdiscovery.org.
  • 6 Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: jsedy@anaptysbio.com.
PMID: 35320716 DOI: 10.1016/j.celrep.2022.110553
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.

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