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Novel role of platelet endothelial cell adhesion molecule-1 (PECAM-1) in facilitating TGF-beta-mediated inhibition of T cell function
  1. Debra Newman1,
  2. Tamara Adams1,
  3. Vidhyalakshmi Arumugam1,
  4. Theresa Bluemn1,
  5. Guoping Fu1 and
  6. Matthew Riese2
  1. Aff1 grid.280427.b000000040434015XBlood Research InstituteBlood Center of Wisconsin Milwaukee WI USA
  2. Aff2 grid.30760.320000000121118460Medical College of Wisconsin Milwaukee WI USA

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Meeting abstracts

Transforming Growth Factor β (TGFb) is an immunosuppressive cytokine that inhibits pro-inflammatory functions of T cells, and is a major contributor to abrogating TH1 and cytotoxic T cell activity against tumors. While canonical signal transduction through effector Smads has been well-defined as a requirement for TGFb-mediated inhibition of T cells, essential non-canonical pathways have not, to date, been defined. This abstract describes the identification of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), CD31, as a novel facilitator of non-canonical TGFβ signal transduction in T cells. Subcutaneously injected tumor cells known to require TGFβ-mediated suppression of immunity for clearance grew more slowly in PECAM-1-/- mice relative to wild type counterparts, and T cells isolated from PECAM-1-/- mice demonstrated relative insensitivity to TGFβ-induced inhibition of IFNγ production and proliferation. Similarly, human T cells lacking PECAM-1 expression demonstrated decreased sensitivity to TGFβ in a manner that could be partially restored by re-expression of PECAM-1. Phosphorylation of PECAM-1 on an Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) and resultant binding of the inhibitory Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) was observed after co-incubation of T cells with TGFβ and anti-CD3, and inducible co-localization of PECAM-1 with the TGFβ receptor complex was identified using co-immunoprecipitation, confocal microscopy and proximity ligation assays. These studies indicate an unexpected role for PECAM-1 in enhancing crucial inhibitory functions of TGFβ in T cells and suggest that targeting of the PECAM-1/TGFβ inhibitory axis represents a novel means to overcome TGFβ-dependent immunosuppression within the tumor microenvironment.