p53 keeps bystanders at the gates

Abstract

The inappropriate expansion of self-reactive "bystander" T cells can contribute to autoimmune disease. In this issue of Immunity, Watanabe et al. (2014) demonstrate that the tumor suppressor p53 prevents the cytokine-dependent proliferation of T cells in the absence of cognate antigens.

Figure 1.. The Tumor Suppressor p53 Blocks Bystander T Cell Proliferation Triggered by IL-2

(upper left) In response to a pathogenic challenge, CD4⁺ T cells that are not specific for antigen are exposed to mitogenic cytokines such as IL-2. In normal animals, IL-2-dependent signals increase the abundance of p53 protein, blocking the proliferation of these “bystander” T cells. (upper right) T cells that lack functional p53 proliferate when exposed to IL-2, even in the absence of TCR signaling, confirming the essential role of p53 in the enforcement of this checkpoint. (bottom right) The specific recognition of antigen (pMHC) by the TCR increases the concentration of the mRNA encoding Mdm2, a ubiquitin ligase that targets p53 for proteasomal degradation. The ensuing degradation of p53 enables the expansion of antigen-specific T cell clones while ensuring that potentially self-reactive “bystander” cells do not participate in the immune response.