Modulation of TCR signaling by beta 1 integrins: role of the tyrosine phosphatase SHP-1

When cross-linked, beta 1 integrins co-activate T cells together with a TCR -CD3 signal. Soluble anti-beta 1 monoclonal antibodies, however, inhibit T cell activation. We report inhibition of early tyrosine kinases, including ZAP-70, p59(fyn), CD4-associated p56(lck) and TCR components under this con dition. The tyrosine phosphatase SHP-1 is activated by engagement of beta 1 integrins and is implicated in this negative regulation since no inhibitio n occurs in SHP-1 dominant-negative T cells. As shown by the use of Lck-def icient cells, the activation of the protein tyrosine phosphatase depends on a pool of p56(lck) that is not associated with CD4. These cross-talk event s were also observed with the alpha 4 beta 1 integrin ligand, VCAM-1. We pr opose that these results may be important in terms of lymphocyte circulatio n; while T cells migrate through the vascular endothelium, they are primed for an amplified response; as inflammation develops, a local accumulation o f soluble integrin ligands may help to turn it off.