Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP)

The hematopoietic tyrosine Phosphatase (HePTP) is predominantly expressed in thymocytes and T lymphocytes and at lower levels in other hematopoietic cells. Expression of the gene is enhanced by the T cell growth factor interleukin-2, suggesting a role for HePTP in T cell proliferation or differentiation. We report that HePTP blocks T cell antigen receptor (TCR)-induced transcriptional activation of a reporter gene driven by a nuclear factor of activated T cells(NFAT)/AP-1 element taken from the interleukin-2 gene promoter. This effect was specific to HePTP and was abolished by a mutation (C270S) that impaired its Phosphatase activity. Co-expression of HePTP also reduced TCR-induced activation of the mitogen-activated protein kinase ERK2 and the TCR-induced appearance of phosphorylated ERK. In contrast, HePTP did not affect the activation of the N-terminal c-Jun kinase, JNK. Together these findings suggest that HePTP plays an active negative role in TCR signaling by dephosphorylating one or several signaling molecules between the receptor and the mitogen-activated protein kinase pathway.