Faculty Collaboration Database

The adhesion molecule PECAM-1 enhances the TGF-β-mediated inhibition of T cell function. Sci Signal 2016 Mar 08;9(418):ra27

Date

03/10/2016

Pubmed ID

26956486

Pubmed Central ID

PMC5087802

DOI

10.1126/scisignal.aad1242

Scopus ID

2-s2.0-84960380725 (requires institutional sign-in at Scopus site)   17 Citations

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.

Author List

Newman DK, Fu G, Adams T, Cui W, Arumugam V, Bluemn T, Riese MJ

Authors

Theresa Bluemn Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Motifs
Animals
Granzymes
Humans
Interferon-gamma
Mice
Mice, Knockout
Platelet Endothelial Cell Adhesion Molecule-1
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Receptors, Transforming Growth Factor beta
Smad Proteins
T-Lymphocytes
Transforming Growth Factor beta