Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells

Immunity. 2016 Nov 15;45(5):1066-1077. doi: 10.1016/j.immuni.2016.10.008. Epub 2016 Oct 25.

Abstract

Dendritic cells (DCs) initiate immunity and also antigen-specific tolerance mediated by extrathymic regulatory T (Treg) cells, yet it remains unclear how DCs regulate induction of such tolerance. Here, we report that efficient induction of Treg cells was instructed by BTLA+DEC205+CD8+CD11c+ DCs and the immunomodulatory functions of BTLA. In contrast, T cell activation in steady state by total CD11c+ DCs that include a majority of DCs that do not express BTLA did not induce Treg cells and had no lasting impact on subsequent immune responses. Engagement of HVEM, a receptor of BTLA, promoted Foxp3 expression in T cells through upregulation of CD5. In contrast, T cells activated in the absence of BTLA and HVEM-mediated functions remained CD5lo and therefore failed to resist the inhibition of Foxp3 expression in response to effector cell-differentiating cytokines. Thus, DCs require BTLA and CD5-dependent mechanisms to actively adjust tolerizing T cell responses under steady-state conditions.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Dendritic Cells / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Flow Cytometry
  • Immune Tolerance / immunology*
  • Immunoblotting
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Real-Time Polymerase Chain Reaction
  • Receptors, Immunologic / immunology*
  • Receptors, Tumor Necrosis Factor, Member 14 / immunology*
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • BTLA protein, mouse
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • Tnfrsf14 protein, mouse