Decreased signaling through the T cell receptor at the thymic level causes rheumatoid arthritis in the SKG mouse -which carries a mutation of ZAP-70 able to impair the activation of the kinase- as well as in human patients carrying sporadic mutations of ZAP-70. We reported that the low molecular weight protein tyrosine phosphatase (LMPTP) is a positive regulator of T cell receptor signaling. In T cells LMPTP is able to dephosphorylate the tyrosine kinase ZAP-70 on the negative regulatory Tyr-292, and increase ZAP-70 activation after TCR engagement. In this proposal we will test the hypothesis that increased expression of LMPTP at the thymic level under control of the LCK proximal promoter is able to rescue the arthritis phenotype of SKG mice. As a result of our experiments we expect to confirm the relevance of LMPTP as a modulator of ZAP-70 and T cell receptor signaling, and validate the LMPTP as a candidate gene/genetic modifier in rheumatoid arthritis. ? ? ? ?
