The role of p53 in antigen-specific and bystander T cell proliferative responses (50.15)

Abstract

Abstract p53 is a tumor suppressor that triggers cell cycle arrest or apoptosis in response to DNA damage or oncogenic signals. The role of p53 in regulating survival and proliferation of normal somatic cells such as T cells, which undergo extensive proliferation, has not been extensively characterized. We observed that the number of peripheral memory phenotype (CD44hi) CD4 T cells is increased in p53 KO mice, suggesting that p53 might have a role in regulating this population. To investigate the role of p53 in regulating T cell activation and proliferation, we analyzed KLH-specific CD4 T cell clones from p53 KO and wild-type mice. WT and p53 KO clones showed similar antigen-specific proliferative response to stimulation with KLH/APC + IL-2. In contrast, p53 KO clones proliferated extensively in response to cytokine in the absence of KLH/APC, while WT clones did not respond to cytokines alone. These results suggested that p53 might prevent antigen-nonspecific (bystander) responses to cytokine in the absence of concomitant antigen-specific signaling. In vitro experiments demonstrated that wild-type KLH-specific CD4 T cell clones do not proliferate as bystanders in co-culture with responding OVA-specific T cells. In contrast, p53 KO clones exhibit extensive bystander proliferation, indicating a role of p53 in preventing antigen-non-specific bystander proliferation. We are currently investigating molecular mechanisms mediating p53 regulation of responses to cytokine signaling.