Antigen-independent, integrin-mediated T cell activation.
The "outside-in" signals produced by the interaction of integrin molecules with the extracellular matrix (ECM) trigger a multitude of cellular events. The vitronectin receptor (VNR), an alpha v beta 3 heterodimer, functions as a costimulatory molecule for the activation of a subset of V gamma 1.1/C gamma 4-bearing gamma/delta T cells, which have been postulated to recognize a ubiquitous self-antigen. We addressed the question of whether stimulation of these T cells requires both engagement of the VNR by ECM proteins and engagement of the TCR by its Ag. We introduced into a TCR- but VNR+ mutant T cell hybridoma, TG40 (derived from 2B4), a chimeric molecule that contains the cytoplasmic tail of the TCR zeta-chain fused to the cytoplasmic and transmembrane region of either human CD8 or human CD25. The transfectants expressing the chimeric molecules secreted IL-2 constitutively when the VNR was engaged with a ligand, e.g., provided by ECM proteins present in FCS. This constitutive cytokine secretion could be blocked with mAb directed against the VNR, with or the peptide RGD, or by growth in serum-free medium. VNR-mediated cell activation also induced the phosphorylation of the zeta-chain. Signaling through the zeta-chain was required, as cells transfected with a chimera containing only a 22 amino-acid long, truncated zeta-chain did not secrete IL-2 constitutively. Thus, we demonstrated that the binding of the VNR to ECM protein in the presence of the zeta-chain is sufficient to induce cytokine secretion by T cells and does not require the recognition of an Ag by the TCR. Such integrin-mediated, Ag-independent activation of T cells may play a critical role in the potentiation of inflammatory responses.
Sturmhöfel
K
K
Laboratory of Molecular Structure, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Brando
C
C
Martinon
F
F
Shevach
E M
EM
Coligan
J E
JE
D000818:Animals; D000941:Antigens / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D016023:Integrins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism; D016024:Receptors, Cytoadhesin / Q000276:immunology; D019030:Receptors, Vitronectin; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D000941:Antigens; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D016023:Integrins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016024:Receptors, Cytoadhesin; D019030:Receptors, Vitronectin