Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2-responding CD4 T cells.

Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4 T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4 T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4 T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4 T cells, Nrp1 expression was assessed and following AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4 T cells increases over the course of activation and proliferation . The actively dividing Nrp1Foxp3 cells express the classic effector phenotype of CD44CD45RB, and the increase in Nrp1Foxp3 cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4 T cells. The downregulation of Nrp1 on CD4 T cells was recapitulated in cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4Foxp3 cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression both and . Collectively, the data demonstrate that Nrp1 is a CD4 T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4 T cell responses.