AhR activation increases IL-2 production by alloreactive CD4 + T cells initiating the differentiation of mucosal-homing Tim3 + Lag3 + Tr1 cells

Eur J Immunol. 2017 Nov;47(11):1989-2001. doi: 10.1002/eji.201747121. Epub 2017 Sep 15.

Abstract

Activation of the aryl hydrocarbon receptor (AhR) by immunosuppressive ligands promotes the development of regulatory T (Treg) cells. Although AhR-induced Foxp3+ Treg cells have been well studied, much less is known about the development and fate of AhR-induced Type 1 Treg (AhR-Tr1) cells. In the current study, we identified the unique transcriptional and functional changes in murine CD4+ T cells that accompany the differentiation of AhR-Tr1 cells during the CD4+ T-cell-dependent phase of an allospecific cytotoxic T lymphocyte (allo-CTL) response. AhR activation increased the expression of genes involved in T-cell activation, immune regulation and chemotaxis, as well as a global downregulation of genes involved in cell cycling. Increased IL-2 production was responsible for the early AhR-Tr1 activation phenotype previously characterized as CD25+ CTLA4+ GITR+ on day 2. The AhR-Tr1 phenotype was further defined by the coexpression of the immunoregulatory receptors Lag3 and Tim3 and non-overlapping expression of CCR4 and CCR9. Consistent with the increased expression of CCR9, real-time imaging showed enhanced migration of AhR-Tr1 cells to the lamina propria of the small intestine and colon. The discovery of mucosal imprinting of AhR-Tr1 cells provides an additional mechanism by which therapeutic AhR ligands can control immunopathology.

Keywords: AhR; CD4+ T cells; IL-2; Lag3; Migration; Tim3; Tr1 cells.

Publication types

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

MeSH terms

  • Allografts
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation / immunology*
  • Cell Movement / immunology
  • Interleukin-2 / biosynthesis*
  • Intestinal Mucosa / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Aryl Hydrocarbon / immunology*
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Interleukin-2
  • Receptors, Aryl Hydrocarbon