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- Title
CD28 ligation induces transplantation tolerance by IFN-gamma-dependent depletion of T cells that recognize alloantigens.
- Authors
Yu, Xue-Zhong; Albert, Michael H; Martin, Paul J; Anasetti, Claudio
- Abstract
Administration of an agonistic anti-CD28 mAb paradoxically inhibits donor T cell expansion and prevents graft-versus-host disease (GVHD) in mice. Here we examined the mechanism of anti-CD28-mediated immunosuppression and found that anti-CD28 mAb activated, rather than blocked, CD28-mediated signaling in vivo. Anti-CD28 treatment prevented GVHD by selectively depleting alloantigen-activated donor T cells through apoptosis but spared the T cells that did not recognize recipient alloantigens. Overexpression of Bcl-x(L) did not protect T cells from depletion and did not affect GVHD prevention after anti-CD28 treatment. Depletion of activated T cells mediated through CD28 did not depend on the expression of death receptors Fas and TNF receptors type I and II, but both the depletion of activated T cells and the suppressive effect of anti-CD28 mAb on GVHD lethality required donor-derived IFN-gamma production. This study demonstrates that agonistic Ab's specific for the CD28 costimulatory molecule may be used as novel therapeutic agents to abrogate pathogenic T cell responses by selective depletion of activated T cells.
- Publication
The Journal of clinical investigation, 2004, Vol 113, Issue 11, p1624
- ISSN
0021-9738
- Publication type
Journal Article
- DOI
10.1172/JCI20940