The inhibitory receptor BTLA controls γδ T cell homeostasis and inflammatory responses

Immunity. 2013 Dec 12;39(6):1082-1094. doi: 10.1016/j.immuni.2013.10.017. Epub 2013 Dec 5.

Abstract

γδ T cells rapidly secrete inflammatory cytokines at barrier sites that aid in protection from pathogens, but mechanisms limiting inflammatory damage remain unclear. We found that retinoid-related orphan receptor gamma-t (RORγt) and interleukin-7 (IL-7) influence γδ T cell homeostasis and function by regulating expression of the inhibitory receptor, B and T lymphocyte attenuator (BTLA). The transcription factor RORγt, via its activating function-2 domain, repressed Btla transcription, whereas IL-7 increased BTLA levels on the cell surface. BTLA expression limited γδ T cell numbers and sustained normal γδ T cell subset frequencies by restricting IL-7 responsiveness and expansion of the CD27(-)RORγt(+) population. BTLA also negatively regulated IL-17 and TNF production in CD27(-) γδ T cells. Consequently, BTLA-deficient mice exhibit enhanced disease in a γδ T cell-dependent model of dermatitis, whereas BTLA agonism reduced inflammation. Therefore, by coordinating expression of BTLA, RORγt and IL-7 balance suppressive and activation stimuli to regulate γδ T cell homeostasis and inflammatory responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Flow Cytometry
  • Gene Deletion
  • Homeostasis*
  • Humans
  • Inflammation*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • BTLA protein, mouse
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Immunologic