Abstract B1: p53 isoforms, Δ133p53 and p53β, regulate aging-associated T lymphocyte senescence.

Abstract

Abstract Normal human cells undergo finite divisions and reach a state of cellular senescence, which is a critical barrier for tumor progression in vivo and contributes to organismal aging. CD8+ T lymphocytes are an excellent model to study cellular senescence in vivo. The decreased proliferative potential and cellular senescence of CD8+ T lymphocytes are associated with loss of CD28 and gain of CD57 cell surface antigens, but the mechanisms regulating these phenotypic changes are unknown. The natural isoforms of human p53 protein, Δ133p53 and p53β, play important roles in regulating replicative cellular senescence in vitro (e.g., in normal human fibroblasts) and in vivo (e.g., in colon adenomas) and in different cell types (mesenchymal and epithelial origins). In this study we show that Δ133p53 and p53β are associated with and regulate replicative cellular senescence in CD8+ T lymphocytes (hematopoietic origin), which represent a physiological setting of in vivo cellular senescence. Loss of CD28 and gain of CD57 in CD8+ T lymphocytes were associated with increased donor age in normal individuals. When stimulated to proliferate in vitro, the FACS sorted CD28+/CD57− subsets of CD8+ T lymphocytes showed highest proliferation rate, whereas CD28−/CD57+ subsets showed lowest. The loss of proliferative potential of the CD28−/CD57+ cells was also associated with the shorter telomere length than the CD28+/CD57− subsets. Importantly, Δ133p53 and p53β expression levels were significantly changed during cellular senescence of CD8+ T lymphocytes, as observed in human fibroblasts and colon adenomas. Δ133p53 levels were decreased and p53β levels were increased in the senescent CD28−/CD57+ subset compared with the proliferative CD28+/CD57− subset. During in vitro culture, FACS sorted CD8+ T lymphocytes became senescent and lost Δ133p53 expression, which was associated with the loss of CD28 expression. Moreover, in overexpression experiments, p53β cooperated with full-length p53 to inhibit cellular proliferation, and Δ133p53 enhanced the proliferative potential of the CD8+ T lymphocytes, suggesting that the p53 isoforms regulate cellular proliferation and senescence in CD8+ T lymphocytes. Our study provides insight toward understanding the mechanisms regulating physiological aging of normal human circulating T lymphocytes and thus proposes a novel approach for reinstating replicative potential and immune function of the senescent CD8+ T lymphocytes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B1.