The death effector domain protein PEA‐15 negatively regulates T‐cell receptor signaling

PEA‐15 is a death effector domain‐containing phosphoprotein that binds ERK and restricts it to the cytoplasm. PEA‐15 also binds to FADD and thereby blocks apoptosis induced by death receptors. Abnormal expression of PEA‐15 is associated with type II diabetes and some cancers; however, its physiological function remains unclear. To determine the function of PEA‐15 in vivo , we used C57BL/6 mice in which the PEA‐15 coding region was deleted. We thereby found that PEA‐15 regulates T‐cell proliferation. PEA‐15‐null mice did not have altered thymic or splenic lymphocyte cellularity or differentiation. However, PEA‐15 deficient T cells had increased CD3/CD28‐induced nuclear translocation of ERK and increased activation of IL‐2 transcription and secretion in comparison to control wild‐type littermates. Indeed, activation of the T‐cell receptor in wild‐type mice caused PEA‐15 release of ERK. In contrast, overexpression of PEA‐15 in Jurkat T cells blocked nuclear translocation of ERK and IL‐2 transcription. Finally, PEA‐15‐null T cells showed increased IL‐2 dependent proliferation on stimulation. No differences in T cell susceptibility to apoptosis were found. Thus, PEA‐15 is a novel player in T‐cell homeostasis. As such this work may have far reaching implications in understanding how the immune response is controlled.—Pastorino, S., Renganathan, H., Caliva, M. J., Filbert, E. L., Opoku‐Ansah, J., Sulzmaier, F. J., Gawecka, J. E., Werlen, G., Shaw, A. S., Ramos, J. W. The death effector domain protein PEA‐15 negatively regulates T‐cell receptor signaling. FASEB J . 24, 2818–2828 (2010). www.fasebj.org