Research ArticleImmunology

The adhesion molecule PECAM-1 enhances the TGF-β–mediated inhibition of T cell function

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Sci. Signal.  08 Mar 2016:
Vol. 9, Issue 418, pp. ra27
DOI: 10.1126/scisignal.aad1242

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Sticking it to T cells

Because of its immunosuppressive effects and abundance in tumor microenvironments, the cytokine transforming growth factor–β (TGF-β) inhibits the antitumor activities of T cells. Targeting TGF-β systemically would interfere with other functions of TGF-β; thus, therapies that block the effects of TGF-β specifically on T cells are needed. Newman et al. found that T cells without the adhesion molecule PECAM-1 were less sensitive to the TGF-β–mediated inhibition of their function than were PECAM-1–positive cells. In a tumor model, PECAM-1–deficient mice exhibited reduced tumor size compared to wild-type mice. Thus, targeting PECAM-1 may specifically enhance the antitumor activity of T cells.

Abstract

Transforming growth factor–β (TGF-β) is an immunosuppressive cytokine that inhibits the proinflammatory functions of T cells, and it is a major factor in abrogating T cell activity against tumors. Canonical TGF-β signaling results in the activation of Smad proteins, which are transcription factors that regulate target gene expression. We found that the cell surface molecule platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitated noncanonical (Smad-independent) TGF-β signaling in T cells. Subcutaneously injected tumor cells that are dependent on TGF-β–mediated suppression of immunity for growth grew more slowly in PECAM-1−/− mice than in their wild-type counterparts. T cells isolated from PECAM-1−/− mice demonstrated relative insensitivity to the TGF-β–dependent inhibition of interferon-γ (IFN-γ) production, granzyme B synthesis, and cellular proliferation. Similarly, human T cells lacking PECAM-1 demonstrated decreased sensitivity to TGF-β in a manner that was partially restored by reexpression of PECAM-1. Co-incubation of T cells with TGF-β and a T cell–activating antibody resulted in PECAM-1 phosphorylation on an immunoreceptor tyrosine–based inhibitory motif (ITIM) and the recruitment of the inhibitory Src homology 2 (SH2) domain–containing tyrosine phosphatase-2 (SHP-2). Such conditions also induced the colocalization of PECAM-1 with the TGF-β receptor complex as identified by coimmunoprecipitation, confocal microscopy, and proximity ligation assays. These studies indicate a role for PECAM-1 in enhancing the inhibitory functions of TGF-β in T cells and suggest that therapeutic targeting of the PECAM-1–TGF-β inhibitory axis represents a means to overcome TGF-β–dependent immunosuppression within the tumor microenvironment.

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