E2F1 and E2F2 Are Differentially Required for Homeostasis-Driven and Antigen-Induced T Cell Proliferation In Vivo

摘要

Homeostasis-driven T cell proliferation occurs in response to a lymphopenic environment and is mediated by TCR and IL-7 signaling.In this report,we demonstrate a defect in the proliferation of murine naive and memory T cells lacking both E2F1 and E2F2 in response to lymphopenic conditions,suggesting that E2F1 and E2F2 function redundantly downstream of TCR and/or IL-7 signaling during homeostasis-driven proliferation.In contrast,T cell proliferation in response to antigenic stimulation is either unaffected(in vivo)or potentiated(ex vivo)by loss of E2F1 and E2F2,indicating divergent requirements for these E2F factors in T cell proliferation mediated by distinct stimuli.E2F1/E2F2 double knockout(DKO)T cells enter S phase in response to homeostatic signaling,but fail to divide,suggesting that S phase progression is either incomplete or defective.In addition,E2F1/E2F2 DKO mice do not recover normal T cell numbers following exposure to a sublethal dose of radiation,indicating that this defect in homeostasis-driven proliferation is physiologically relevant.Consistent with their failure in cell cycle progression,the differentiation of DKO T cells into memory T cells in response to homeostatic signals is significantly reduced.These observations support the idea that proliferation is required for memory T cell formation and also have implications for the development of clinical strategies to minimize the occurrence of lymphopenia-induced autoimmunity.