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p21^CIP1/WAF1 Controls Proliferation of Activated/Memory T Cells and Affects Homeostasis and Memory T Cell Responses¹

Cristina F. Arias^*, André Ballesteros-Tato^*, María Isabel García^*, Juan Martín-Caballero, Juana M. Flores, Carlos Martínez-A^* and Dimitrios Balomenos^2,*

^* Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Campus de Cantoblanco, Madrid, Spain; Unidad de Animal de Laboratorio, Barcelona Biomedical Research Park, Barcelona, Spain; and Departamento de Medicina y Cirugía, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants to D.B. from the Spanish Ministry of Education and Science (SAF2002-01973 and SAF2005-05264) and the Community of Madrid (07B/0043/2002). Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (Consejo Superior de Investigaciones Cientificas) and by Pfizer. C.F.A. and A.B.-T. received predoctoral fellowships from the Community of Madrid regional government. D.B. is a Ramón y Cajal fellow of the Spanish Ministry of Education and Science.

² Address correspondence and reprint requests to Dr. Dimitrios Balomenos, Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Darwin 3, Campus de Cantoblanco, E-28049 Madrid, Spain. E-mail address: dbalomenos{at}cnb.uam.es

³ Abbreviations used in this paper: LN, lymph node; AICD, activation-induced cell death; FasL, Fas ligand; PI, propidium iodide; wt, wild type.