The Journal of Experimental Medicine
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Published online 14 November 2005 doi:10.1084/jem.20051359
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 10, 1341-1348
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ARTICLE

 Gadd45ß and Gadd45{gamma} are critical for regulating autoimmunity

Lin Liu1, Elise Tran2, Yani Zhao1, Yuchen Huang1, Richard Flavell2,3, and Binfeng Lu1

1 Department of Immunology, University of Pittsburgh School of Medicine, E1047 BST, Pittsburgh, PA 15261
2 Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
3 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520

CORRESPONDENCE Richard Flavell: richard.flavell{at}yale.edu OR Binfeng Lu: Binfeng{at}pitt.edu

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, ß and {gamma}, are critical in the development of pathogenic effector T cells. CD4+ T cells lacking Gadd45ß 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 Gadd45ß and Gadd45{gamma} spontaneously developed signs of autoimmune lymphoproliferative syndrome and systemic lupus erythematosus. Our findings therefore identify the Gadd45ß/Gadd45{gamma}-mediated control of effector autoimmune lymphocytes as an attractive novel target for autoimmune disease therapy.

Abbreviations used: AICD, activation-induced cell death; CFSE, carboxyfluorescein succinimidyl ester; CNS, central nervous system; dsDNA, double-stranded DNA; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; PAMP, pathogen-associated molecular pattern.

L. Liu, E. Tran, and B. Lu contributed equally to this work.


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