The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1998/7/199/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 1, July 1, 1998 199-204

Brief Definitive Reports

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Blockade Accelerates the Acute Rejection of Cardiac Allografts in CD28-deficient Mice: CTLA4 Can Function Independently of CD28

Hua Lin*, Jeffrey C. Rathmell{ddagger}, Gary S. Gray§, Craig B. Thompson*,{ddagger}, Jeffrey M. Leiden*, and Maria-Luisa Alegre*

From the * Department of Medicine, and the {ddagger} Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637; and the § Genetics Institute, Cambridge, Massachusetts 02140

Cytotoxic T lymphocyte antigen 4 (CTLA4) appears to negatively regulate T cell activation. One mechanism by which CTLA4 might antagonize T cell function is through inhibition of CD28 signaling by competing for their shared ligands B7-1 and B7-2. In addition, CTLA4 ligation could initiate a signaling cascade that inhibits T cell activation. To address whether CTLA4 could inhibit immune responses in the absence of CD28, rejection of heart allografts was studied in CD28-deficient mice. H-2q hearts were transplanted into allogeneic wild-type or CD28-deficient mice (H-2b). Graft rejection was delayed in CD28-deficient compared with wild-type mice. Treatment of wild-type recipients with CTLA4-immunoglobulin (Ig), or with anti–B7-1 plus anti–B7-2 mAbs significantly prolonged allograft survival. In contrast, treatment of CD28-deficient mice with CTLA4-Ig, anti–B7-1 plus anti–B7-2 mAbs, or a blocking anti-CTLA4 mAb induced acceleration of allograft rejection. This increased rate of graft rejection was associated with more severe mononuclear cell infiltration and enhanced levels of IFN-{gamma} and IL-6 transcripts in donor hearts of untreated wild-type and CTLA4-Ig– or anti-CTLA4 mAb–treated CD28-deficient mice. Thus, the negative regulatory role of CTLA4 extends beyond its potential ability to prevent CD28 activation through ligand competition. Even in the absence of CD28, CTLA4 plays an inhibitory role in the regulation of allograft rejection.

Key Words: cytotoxic T lymphocyte antigen 4 • CD28-deficient • cytotoxic T lymphocyte antigen 4–immunoglobulin • transplantation • T lymphocyte

Address correspondence to Maria-Luisa Alegre, Gwen Knapp Center for Lupus and Immunology Research, 924 East 57th St., R402, Chicago, IL 60637-5420. Phone: 773-702-4188; Fax: 773-702-1576; E-mail: malegre @


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