p21CIP1/WAF1 controls proliferation of activated/memory T cells and affects homeostasis and memory T cell responses.
Development of autoantibodies and lupus-like autoimmunity by 129/Sv x 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.
Arias
Cristina F
CF
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Campus de Cantoblanco, Madrid, Spain.
Ballesteros-Tato
André
A
García
María Isabel
MI
Martín-Caballero
Juan
J
Flores
Juana M
JM
Martínez-A
Carlos
C
Balomenos
Dimitrios
D
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D007156:Immunologic Memory / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21