The Journal of Experimental Medicine
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Published 3 December 2001. doi:10.1084/jem.194.11.1675
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© Rockefeller University Press, 0022-1007/2001/12/1675/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 11, December 3, 2001 1675-1682

Brief Definitive Report

Cytotoxic T Lymphocyte Antigen 4 and CD28 Modulate Cell Surface Raft Expression in Their Regulation of T Cell Function

Margarita Martin1,2, Helga Schneider1,3,4, Abdallah Azouz1,3 and Christopher E. Rudd1,2,4

1 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
2 Department of Pathology, Harvard Medical School, Boston, MA 02115
3 Department of Medicine, Harvard Medical School, Boston, MA 02115
4 Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom

Address correspondence to C.E. Rudd, Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Rd., London W12 ONN, UK. Phone: 020-8383-8421; Fax: 020-8383-8434; E-mail: c.rudd{at}ic.ac.uk

Coreceptors CD28 and cytotoxic T lymphocyte antigen (CTLA)-4 have opposing effects on TcR/CD3 activation of T cells. While CD28 enhances and CTLA-4 inhibits activation, the underlying molecular basis of these effects has yet to be established. In this context, ganglioside and cholesterol enriched membrane microdomains (rafts, GEMs) serve as centers of signaling in T cells. Although CD28 can promote TcR/raft colocalization, evidence is lacking on whether the surface expression of membrane rafts can be targeted by CTLA-4 in its modulation of T cell responses. In this study, we demonstrate that both CD28 and CTLA-4 profoundly alter the surface expression of membrane rafts during T cell activation. While CD28 increased expression and the number of peripheral T cells induced to express surface rafts in response to TcR ligation, CTLA-4 potently inhibited both TcR and TcR x CD28 induced raft expression on the surface of T cells. Consistent with this, CD28 increased the presence of the linker of activated T cells (LAT) in purified membrane rafts, while CTLA-4 coligation effectively blocked this increase. Further, the reversal of the CTLA-4 block with CD3/CD28 ligation was accompanied by an increase in surface raft expression and associated LAT. Our observations demonstrate for the first time that CTLA-4 targets the release of rafts to the surface of T cells, and provides a mechanism for the opposing effects of CD28 and CTLA-4 on costimulation.

Key Words: T cell function • CD28 • CTLA-4 • lipid rafts • LAT


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