RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 9 May 2014; doi:10.1038/nri3687
T CELL SIGNALLING
p53 controls the crowd
p53 directly prevents cytokinedriven, antigennonspecific … T cell proliferation
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. 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 prolif eration 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 prolif eration 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. Kirsty Minton ORIGINAL RESEARCH PAPER Watanabe, M. et al. Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4+ T cell responses. Immunity http://dx.doi. org/101.1016/j.immuni.2014.04.006 (2014)
NPG
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | JUNE 2014 © 2014 Macmillan Publishers Limited. All rights reserved
T CELL SIGNALLING
p53 controls the crowd
p53 directly prevents cytokinedriven, antigennonspecific … T cell proliferation
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. 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 prolif eration 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 prolif eration 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. Kirsty Minton ORIGINAL RESEARCH PAPER Watanabe, M. et al. Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4+ T cell responses. Immunity http://dx.doi. org/101.1016/j.immuni.2014.04.006 (2014)
NPG
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | JUNE 2014 © 2014 Macmillan Publishers Limited. All rights reserved
