TGF-beta abrogates TCR-mediated signaling by upregulating tyrosine phosphatases in T cells

TGF-beta is known to inhibit many of the immune cell functions including T cell proliferation and IL-2 production. The mechanism of such TGF-beta -med iated inhibition of T cell functions is poorly understood. The present stud y examined the effects of TGF-beta on the activation of protein tyrosine ki nases (PTK) P56(lck), P59(fyn), and Zap-70, and protein tyrosine phosphatas es (PTP) SHP-1 and SHP-2. A balance between the actions of PTK and PTP is c ritical for appropriate T cell activation. These studies were carried out u sing nylon wool-purified splenic T cells from healthy Sprague-Dawley rats. Results from these studies showed that incubation of T cells with TGF-beta inhibited the activation of P56(lck), P59(fyn), and Zap-70. The decrease in these three protein tyrosine kinases was accompanied by an increase in the activation of the protein tyrosine phosphatase SHP-1. There was no change in the phosphorylation of SHP-2 with and without pretreatment of T cells wi th TGF-beta. The decrease in P56(lck), P59(fyn) kinase activity, and Zap-70 phosphorylation was prevented when T cells were stimulated with anti-CDS i n the presence of pervanadate, an inhibitor of PTP. These results suggested that TGF-beta -mediated inhibition of P56(lck), P59(fyn), and Zap-70 is li kely due to an up-regulation of protein tyrosine phosphatases such as SHP-1 .