The adhesion molecule PECAM-1 enhances the TGF-?-mediated inhibition of T cell function.

ABSTRACT: Transforming growth factor-? (TGF-?) 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-? 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-? signaling in T cells. Subcutaneously injected tumor cells that are dependent on TGF-?-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-?-dependent inhibition of interferon-? (IFN-?) production, granzyme B synthesis, and cellular proliferation. Similarly, human T cells lacking PECAM-1 demonstrated decreased sensitivity to TGF-? in a manner that was partially restored by reexpression of PECAM-1. Co-incubation of T cells with TGF-? 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-? 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-? in T cells and suggest that therapeutic targeting of the PECAM-1-TGF-? inhibitory axis represents a means to overcome TGF-?-dependent immunosuppression within the tumor microenvironment.

SUBMITTER: Newman DK 

PROVIDER: S-EPMC5087802 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature