Editors' ChoiceImmunology

p53 Keeps Immune Responses Specific

Sci. Signal.  27 May 2014:
Vol. 7, Issue 327, pp. ec144
DOI: 10.1126/scisignal.2005515

To become fully activated, T cells receive antigen-specific signals through their T cell receptors (TCRs) and coreceptors by interacting with antigen-presenting cells (APCs). Cytokines, such as interleukin-2 (IL-2), generate a third signal that then stimulates T cell proliferation. Understanding the mechanism by which only antigen-exposed T cells, but not bystander cells, proliferate in response to IL-2 could help in designing therapies to prevent inappropriate immune responses. Watanabe et al. found that, whereas T cells from both wild-type mice and mice deficient in the tumor suppressor protein p53 proliferated similarly in response to costimulation with antigen-loaded APCs and IL-2, only the p53-deficient T cells proliferated in response to IL-2 alone. Flow cytometric and biochemical analyses showed that there were no differences in the amounts of IL-2 receptor subunits or in the extent of IL-2 signaling between wild-type and p53-deficient T cells. Compared with wild-type T cells, p53-deficient T cells showed increased DNA synthesis and enhanced cell division when costimulated with antigen-loaded APCs and IL-2. Stimulation of wild-type T cells through the TCR alone led to a transient increase, but then a substantial decrease in p53 abundance, whereas stimulation of T cells with IL-2 alone did not reduce p53 abundance. In addition, stimulation of wild-type T cells through the TCR, but not the IL-2 receptor, increased the mRNA and protein abundance of Mdm2, an E3 ubiquitin ligase that targets p53 for degradation. Exposure of wild-type T cells to the Mdm2 inhibitor Nutlin3a prevented the loss of p53 and blocked proliferation in response to antigen-loaded APCs and IL-2. When wild-type mouse CD4+ T cells that had been exposed to antigen in vivo were isolated and stimulated with antigen in vitro, their proliferation was blocked by Nutlin3a. Together, these data suggest that p53 acts in T cells to block inappropriate proliferation in response to IL-2 until the cells receive antigen-specific signals.

M. Watanabe, K. D. Moon, M. S. Vacchio, K. S. Hathcock, R. J. Hodes, Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4+ T cell responses. Immunity 40, 1–11 (2014). [PubMed]

M. A. Fray, S. C. Bunnell, p53 keeps bystanders at the gates. Immunity 40, 633–635 (2014). [PubMed]