title: Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production.
abstract: Self/non-self discrimination characterizes immunity and allows responses against pathogens but not self-antigens. Understanding the principles that govern this process is essential for designing autoimmunity treatments. p21 is thought to attenuate autoreactivity by limiting T cell expansion. Here, we provide direct evidence for a p21 role in controlling autoimmune T cell autoreactivity without affecting normal T cell responses. We studied C57BL/6, C57BL/6/lpr and MRL/lpr mice overexpressing p21 in T cells, and showed reduced autoreactivity and lymphadenopathy in C57BL/6/lpr, and reduced mortality in MRL/lpr mice. p21 inhibited effector/memory CD4(+) CD8(+) and CD4(-)CD8(-) lpr T cell accumulation without altering defective lpr apoptosis. This was mediated by a previously non-described p21 function in limiting T cell overactivation and overproduction of IFN-γ, a key lupus cytokine. p21 did not affect normal T cell responses, revealing differential p21 requirements for autoreactive and normal T cell activity regulation. The underlying concept of these findings suggests potential treatments for lupus and autoimmune lymphoproliferative syndrome, without compromising normal immunity.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Daszkiewicz
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vázquez-Mateo
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Gorjana
authors.initials: G
authors.lastname: Rackov
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: André
authors.initials: A
authors.lastname: Ballesteros-Tato
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Weber
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Madrigal-Avilés
authors.affiliation: Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Pilato
authors.affiliation: Cancer Cell Biology Program, Sidney Kimmel Cancer Center, San Diego, CA, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Fotedar
authors.affiliation: Sanford-Burnham Medical Research Institute, San Diego, CA, USA.
authors.forename: Rati
authors.initials: R
authors.lastname: Fotedar
authors.affiliation: Animal Biology Department, School of Veterinary Medicine, Universidad Complutense, Madrid, Spain.
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.affiliation: Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-A
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Balomenos
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D010047:Ovalbumin / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014616:Vaccinia virus / Q000276:immunology
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D007371:Interferon-gamma; D010047:Ovalbumin