Editors' ChoiceImmunology

TRPV1 Activates T Cells

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Science Signaling  28 Oct 2014:
Vol. 7, Issue 349, pp. ec301
DOI: 10.1126/scisignal.aaa1571

Stimulation of the T cell receptor (TCR) in CD4+ T cells leads to the activation of store-operated calcium channels in the plasma membrane, influx of calcium, activation of the transcription factors nuclear factor of activated T cells (NFAT) and nuclear factor κB (NF-κB), and production of inflammatory cytokines. Bertin et al. investigated whether other plasma membrane calcium channels contributed to T cell activation. Flow cytometry and confocal microscopy analyses showed that TRPV1, a member of the vanilloid subfamily of transient receptor potential (TRP) channels, was found mostly at the plasma membrane of mouse and human CD4+ T cells. TRPV1 is best characterized as a pain receptor in sensory neurons. Patch-clamp assays demonstrated that the TRPV1 agonist capsaicin stimulated calcium currents in CD4+ T cells from wild-type (WT) mice, but not TRPV1-deficient (Trpv1–/–) mice. TCR-stimulated calcium flux in TRPV1-deficient CD4+ T cells was decreased compared to that in WT CD4+ T cells. Confocal microscopy studies showed that TRPV1 associated with the TCR co-receptor CD4 and the nonreceptor tyrosine kinase Lck in resting CD4+ T cells. In response to TCR stimulation, TRPV1 and Lck were recruited to TCR microclusters, and this recruitment depended on the phosphorylation of TRPV1 by Lck. The activation of NFAT and NF-κB was decreased in TCR-stimulated TRPV1-deficient CD4+ T cells compared to that in TCR-stimulated WT CD4+ T cells. As a consequence, TRPV1-deficient T cells secreted less effector cytokines, such as interleukin-2 (IL-2) and interferon-γ (IFN-γ), than did WT CD4+ T cells. In addition, exposure of human CD4+ T cells to a TRPV1 antagonist inhibited their production of IL-2 in response to TCR stimulation. Finally, analysis of mouse models of colitis, an inflammatory intestinal disease, showed that TRPV1 in CD4+ T cells contributed to increased disease severity and decreased survival. Together, these data suggest that TRPV1 contributes to T cell activation and inflammatory cytokine production and that targeting this channel may provide a therapy to inhibit proinflammatory T cell responses.

S. Bertin, Y. Aoki-Nonaka, P. R. de Jong, L. L. Nohara, H. Xu, S. R. Stanwood, S. Srikanth, J. Lee, K. To, L. Abramson, T. Yu, T. Han, R. Touma, X. Li, J. M. González-Navajas, S. Herdman, M. Corr, G. Fu, H. Dong, Y. Gwack, A. Franco, W. A. Jefferies, E. Raz, The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4+ T cells. Nat. Immunol. 15, 1055–1063 (2014). [PubMed]

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