Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 105 (2): 635-640

Copyright © 2008 by the National Academy of Sciences.


Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily

Kausik Chattopadhyay*, Udupi A. Ramagopal{dagger}, Michael Brenowitz{dagger}, Stanley G. Nathenson*,{ddagger},§, and Steven C. Almo{dagger},§

Departments of *Microbiology and Immunology, {ddagger}Cell Biology, {dagger}Biochemistry, and Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461

Contributed by Stanley G. Nathenson, November 6, 2007

Received for publication August 3, 2007.

Abstract: Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. In contrast to all previously characterized homotrimeric TNF family members, the mouse GITRL crystal structure reveals a previously unrecognized dimeric assembly that is stabilized via a unique "domain-swapping" interaction. Consistent with its crystal structure, mouse GITRL exists as a stable dimer in solution. Structure-guided mutagenesis studies confirmed the determinants responsible for dimerization and support a previously unrecognized receptor-recognition surface for mouse GITRL that has not been observed for any other TNF family members. Taken together, the unique structural and biochemical behavior of mouse GITRL, along with the unusual domain organization of murine GITR, support a previously unrecognized mechanism for signaling within the TNF superfamily.

Key Words: crystal structure • domain swap • oligomerization • T cell costimulation

Author contributions: K.C., M.B., S.G.N., and S.C.A. designed research; K.C., U.A.R., and M.B. performed research; K.C. contributed new reagents/analytic tools; K.C., U.A.R., and M.B. analyzed data; and K.C., S.G.N., and S.C.A. wrote the paper.

The authors declare no conflict of interest.

Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, (PDB ID codes 2QDN and 3B9I).

This article contains supporting information online at

§To whom correspondence may be addressed. E-mail: nathenso{at} and almo{at}

© 2008 by The National Academy of Sciences of the USA

GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells.
G. Liao, S. Nayak, J. R. Regueiro, S. B. Berger, C. Detre, X. Romero, R. de Waal Malefyt, T. A. Chatila, R. W. Herzog, and C. Terhorst (2010)
Int. Immunol. 22, 259-270
   Abstract »    Full Text »    PDF »
Trimer Stabilization, Oligomerization, and Antibody-Mediated Cell Surface Immobilization Improve the Activity of Soluble Trimers of CD27L, CD40L, 41BBL, and Glucocorticoid-Induced TNF Receptor Ligand.
A. Wyzgol, N. Muller, A. Fick, S. Munkel, G. U. Grigoleit, K. Pfizenmaier, and H. Wajant (2009)
J. Immunol. 183, 1851-1861
   Abstract »    Full Text »    PDF »
GITR Triggering Induces Expansion of Both Effector and Regulatory CD4+ T Cells In Vivo.
R. W. van Olffen, N. Koning, K. P. J. M. van Gisbergen, F. M. Wensveen, R. M. Hoek, L. Boon, J. Hamann, R. A. W. van Lier, and M. A. Nolte (2009)
J. Immunol. 182, 7490-7500
   Abstract »    Full Text »    PDF »
Human glucocorticoid-induced TNF receptor ligand regulates its signaling activity through multiple oligomerization states.
Z. Zhou, X. Song, A. Berezov, G. Zhang, Y. Li, H. Zhang, R. Murali, B. Li, and M. I. Greene (2008)
PNAS 105, 5465-5470
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882