Gadd45 beta and Gadd45 gamma are critical for regulating autoimmunity.
The number of effector T cells is controlled by proliferation and programmed cell death. Loss of these controls on self-destructive effector T cells may precipitate autoimmunity. Here, we show that two members of the growth arrest and DNA damage-inducible (Gadd45) family, beta and gamma, are critical in the development of pathogenic effector T cells. CD4(+) T cells lacking Gadd45beta can rapidly expand and invade the central nervous system in response to myelin immunization, provoking an exacerbated and prolonged autoimmune encephalomyelitis in mice. Importantly, mice with compound deficiency in Gadd45beta and Gadd45gamma spontaneously developed signs of autoimmune lymphoproliferative syndrome and systemic lupus erythematosus. Our findings therefore identify the Gadd45beta/Gadd45gamma-mediated control of effector autoimmune lymphocytes as an attractive novel target for autoimmune disease therapy.
Liu
Lin
L
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Tran
Elise
E
Zhao
Yani
Y
Huang
Yuchen
Y
Flavell
Richard
R
Lu
Binfeng
B
D000367:Age Factors; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D018417:Th1 Cells; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins; C121373:Gadd45g protein, mouse