Editors' ChoiceImmunology

Calcineurin for T cell adhesion

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Sci. Signal.  07 Feb 2017:
Vol. 10, Issue 465, eaam9146
DOI: 10.1126/scisignal.aam9146

The phosphatase calcineurin not only activates transcription factors but also promotes T cell adhesion upon T cell activation.

Antigen-mediated stimulation of the T cell receptor (TCR) results in the sequential activation of the kinases Lck and ZAP-70 and the phosphorylation of the adaptor molecules LAT and SLP-76, which recruit other adaptors and signaling proteins required for T cell activation, which involves Ca2+ signaling. The resulting increase in the intracellular Ca2+ concentration activates the serine and threonine phosphatase calcineurin, which dephosphorylates and activates members of the NFAT family of transcription factors, which translocate to the nucleus and induce the expression of genes encoding cytokines. By blocking calcineurin activation, the immunosuppressive drugs cyclosporin A (CsA) and FK506 are thought to inhibit NFAT function and T cell activation. Dutta et al. found that CsA and FK506 or calcineurin knockdown inhibited the Lck-mediated phosphorylation of ZAP-70 in TCR-stimulated human T cells. Confocal microscopy and immunoprecipitation studies showed that calcineurin transiently associated with ZAP-70 through a mechanism that required TCR activation and the kinase activity of Lck. Inhibition of calcineurin in TCR-stimulated T cells resulted in the increased phosphorylation of Lck at Ser59. Cells expressing the S59A mutant Lck had enhanced signaling downstream of the TCR compared with that in cells expressing wild-type Lck, suggesting that phosphorylation of Ser59 was inhibitory. Similar to inhibition of Lck, CsA and FK506 inhibited the integrin-dependent adhesion of T cells to coated plates; however, the integrin-mediated adhesion of untreated T cells to the plates was independent of NFAT activity. Together, these data suggest that TCR stimulation results in the recruitment of calcineurin to the TCR complex, where it dephosphorylates Lck at an inhibitory serine, thus enabling TCR signaling and adhesion in an NFAT-independent manner. Thus, these findings establish an alternative mechanism by which CsA and FK506 inhibit T cell activation to suppress the immune response.

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