The integration of signals through the T cell receptor (TCR) and through cytokine receptors is required for the activation and clonal expansion of antigen-specific T cells. New research published in Immunity describes a role for the tumour suppressor protein p53 (which is encoded by Trp53) in preventing the proliferation of CD4+ T cells in response to cytokine stimulation alone, which could be an important mechanism to limit bystander proliferation of nonspecific T cells during an immune response.

Credit: NPG

p53 directly prevents cytokine-driven, antigen-nonspecific ... T cell proliferation

Trp53−/− and wild-type CD4+ T cell clones proliferated to a similar extent after combined stimulation with a specific antigen and interleukin-2 (IL-2), but only the Trp53−/− clones proliferated in response to IL-2 in the absence of antigen. Using T cell clones from p53ER-TAM mice — in which p53 is active only in the presence of 4-hydroxy-tamoxifen (TAM) — the authors showed that clonal proliferation in response to antigen plus IL-2 was similar whether p53 was active or inactive, whereas T cell proliferation in response to IL-2 alone was suppressed by active p53. Thus, p53 directly prevents cytokine-driven, antigen-nonspecific — but not antigen-specific — T cell proliferation.

This suppressive effect of p53 on antigen-independent T cell proliferation could not be explained by differences in the expression of IL-2 receptor components between wild-type and Trp53−/− T cells or by differences in signalling downstream of the IL-2 receptor. In keeping with the role of p53 in preventing cell cycle progression in response to DNA damage, Trp53−/− T cell clones, but not wild-type T cell clones, underwent extensive cell division in response to IL-2 alone; they showed substantial DNA synthesis after IL-2 stimulation and had an increased proportion of cells in the S phase of the cell cycle.

These results show that p53 inhibits IL-2-induced T cell proliferation by cell cycle blockade, which indicates that a mechanism to prevent this suppressive effect operates in antigen-stimulated T cells. The early induction of p53 expression that occurs in T cells after stimulation with antigen and/or IL-2 was sustained in IL-2-stimulated cells but was decreased to baseline levels in cells that were stimulated with antigen and IL-2. Trp53 mRNA levels were significantly lower in antigen-plus-IL-2-stimulated T cells compared with IL-2-stimulated T cells by 96 hours after stimulation. Furthermore, stimulation with antigen plus IL-2, but not IL-2 stimulation alone, induced the expression of mRNA encoding MDM2, which mediates the ubiquitylation and proteasomal degradation of p53. So, p53 levels are downregulated both transcriptionally and post-transcriptionally in antigen-stimulated T cells.

The crucial role of p53 downmodulation in the induction of antigen-specific T cell proliferation was shown using Nutlin 3a, which prevents the MDM2-mediated degradation of p53. Nutlin 3a inhibited the proliferation of wild-type T cells that were stimulated with antigen and IL-2 but had no effect on the proliferation of Trp53−/− T cells in both in vitro and in vivo assays. Thus, the ability of TCR signalling to downregulate p53 expression ensures the antigen specificity of cytokine-driven T cell proliferation.