title: CD28 ligation induces transplantation tolerance by IFN-gamma-dependent depletion of T cells that recognize alloantigens.
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.
authors.affiliation: Human Immunogenetics Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. xyu@fhcrc.org
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Martin
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006086:Graft vs Host Disease / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism*; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D051020:bcl-X Protein
chemical_list: D000906:Antibodies; D018122:B7-1 Antigen; C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D007519:Isoantigens; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D007371:Interferon-gamma