p21CIP1/WAF1 Controls Proliferation of Activated/Memory T Cells and Affects Homeostasis and Memory T Cell Responses

Abstract

Development of autoantibodies and lupus-like autoimmunity by 129/Sv × C57BL/6 p21−/− mice has established that cell cycle deregulation is one the defective pathways leading to break of tolerance. Memory T cell accumulation is thought to be related to tolerance loss in murine lupus models. We studied T cell memory responses in C57BL/6 p21−/− mice that develop lupus-like disease manifestations. p21 did not affect primary proliferation of naive T cells, and was required for cycling control, but not for apoptosis of activated/memory T cells. When we induced apoptosis by secondary TCR challenge, surviving memory T cells depended on p21 for proliferation control. Under conditions of secondary T cell stimulation that did not cause apoptosis, p21 was also needed for regulation of activated/memory T cell expansion. The requirement for p21 in the control of T cell proliferation of activated/memory T cells suggests that in addition to apoptosis, cycling regulation by p21 constitutes a new pathway for T cell homeostasis. Concurring with this view, we found accumulation in p21−/− mice of memory CD4+ T cells that showed increased proliferative potential after TCR stimulation. Furthermore, OVA immunization of p21−/− mice generated hyperresponsive OVA-specific T cells. Overall, the data show that p21 controls the proliferation of only activated/memory T cells, and suggest that p21 forms part of the memory T cell homeostasis mechanism, contributing to maintenance of tolerance.

A regulatory SNP at position −899 in CDKN1A is associated with systemic lupus erythematosus and lupus nephritis

“…18 In the immune system, p21 appears to regulate lymphocyte activation and homeostatic proliferation, as its deficiency enhances proliferation and hyperresponsiveness of memory or activated T-cells. 19 We suggest that the reduced production of p21 by the minor allele A of the À899 SNP is one of the genetic factors contributing to dysregulation of lymphocyte homeostasis and immune tolerance.…”

BTB-ZF Protein Znf131 Regulates Cell Growth of Developing and Mature T Cells

“…Cip1 plays an important role in suppressing excessive proliferation of the effector/memory T cells necessary to avoid the development of autoimmunity (44). This indicates that one of the mechanisms in which Znf131 regulates peripheral T cell proliferation is its suppressive effect on p21 Cip1 expression.…”

“…One of the candidate genes of Znf131 targets turned out to be one of the cdk inhibitors, p21 cip1 , encoded by the cdkn1a gene that is involved in the regulation of cell proliferation, autoimmunity, and tumorigenesis (18,19). p21 has to be appropriately regulated for the immune response; therefore, the proliferative potency of T cells gets uncontrolled in the absence of this gene and eventually develop fatal autoimmune disease (44,(51)(52)(53). In contrast, the enhanced expression in the presence of exogenous p21 in T cells leads to the suppression of the proliferation capacity (54).…”

Cell cycle regulation by FasL and Apo2L/TRAIL in human T-cell blasts. Implications for autoimmune lymphoproliferative syndromes

“…The induction of p21 WAF-1 expression results in cell cycle arrest in the G 2 /M and G 1 /S transitions [17]. On the other hand, it has been demonstrated that p21 WAF-1 is important in the regulation of T-cell proliferation, at least in the secondary response of memory T cells and that p21 WAF-1 knockout mice have a tendency to develop autoimmune disease in greater or lesser extent, depending on their genetic background [28,29]. p21 induction can be mediated through p53-dependent and -independent mechanisms [18].…”