The Journal of Experimental Medicine
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Published online April 14, 2008
doi:10.1084/jem.20071364
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Pappu et al.
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ARTICLE

 TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease

Bhanu P. Pappu1, Anna Borodovsky2, Timothy S. Zheng2, Xuexian Yang1, Ping Wu2, Xingwen Dong2, Shawn Weng2, Beth Browning2, Martin L. Scott2, Li Ma3, Lihe Su2, Qiang Tian3, Pascal Schneider5, Richard A. Flavell4, Chen Dong1, and Linda C. Burkly2

1 Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030
2 Department of Immunobiology and Drug Discovery, Biogen Idec, Cambridge, MA 02142
3 Institute for Systems Biology, Seattle, WA 98103
4 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
5 Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland

CORRESPONDENCE Chen Dong: cdong{at}mdanderson.org OR Linda C. Burkly: linda.burkly{at}biogenidec.com

T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A–DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A–/– dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A–/– animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A–DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

Abbreviations used: BMDC, bone marrow–derived DC; CNS, central nervous system; DR3, death receptor 3; EAE, experimental autoimmune encephalomyelitis; i–T reg cell, TGF-β–induced T reg; MOG, myelin oligodendrocyte glycoprotein; n–T reg cell, naturally occurring T reg cell; PB, peripheral blood.

B.P. Pappu and A. Borodovsky contributed equally to this study.

A. Borodovsky's present address is Alnylam, Cambridge, MA 02142.

M. Scott's present address is Merck Research Laboratories, Boston, MA 02115.


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