TitleAhR activation increases IL-2 production by alloreactive CD4 T cells initiating the differentiation of mucosal-homing Tim3 Lag3 Tr1 cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsEhrlich AK, Pennington JM, Tilton S, Wang X, Marshall NB, Rohlman D, Funatake C, Punj S, O'Donnell E, Yu Z, Kolluri SK, Kerkvliet NI
JournalEur J Immunol
Date Published2017 11
KeywordsAllografts, Animals, CD4-Positive T-Lymphocytes, Cell Differentiation, Cell Movement, Interleukin-2, Intestinal Mucosa, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Aryl Hydrocarbon, T-Lymphocytes, Regulatory

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.

Alternate JournalEur. J. Immunol.
PubMed ID28833046
PubMed Central IDPMC5927372
Grant ListR01 ES016651 / ES / NIEHS NIH HHS / United States
P01 ES000040 / ES / NIEHS NIH HHS / United States
P01ES00210 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States