Abstract
FcR-binding "classical" anti-CD3 mAb is a potent immunosuppressive drug that alters CD4(+) and CD8(+) T cell function in vivo via anergy induction and programmed cell death (PCD). Anti-CD3-mediated PCD was Fas independent but was mediated by the mitochondria-initiated apoptosis that was abrogated in Bcl-x(L)-transgenic T cells. The PCD was more pronounced in CD28-deficient mice consistent with defective Bcl-x(L) up-regulation. Residual T cells isolated from anti-CD3-treated wild-type, CD28(-/-), and Bcl-x(L)-transgenic mice were hyporesponsive. The hyporesponsiveness was more pronounced in CD28(-/-) and wild-type mice treated with anti-B7-2, suggesting that CD28 interaction with B7-2 regulates T cell responsiveness in anti-CD3-treated animals. Finally, anti-CD3 treatment led to indefinite cardiac allograft survival in wild-type but not Bcl-x(L) animals. Together these results implicate CD28/B7 signaling in the regulation of both anti-CD3-induced T cell depletion and hyporesponsiveness in vivo, but T cell depletion, not hyporesponsiveness, appears to be critical for anti-CD3 mAb-mediated long-term immune regulation.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Antibodies, Monoclonal / administration & dosage*
-
Antigens, CD / metabolism
-
Apoptosis / genetics
-
Apoptosis / immunology
-
B7-1 Antigen / physiology*
-
B7-2 Antigen
-
CD28 Antigens / genetics
-
CD28 Antigens / metabolism
-
CD28 Antigens / physiology*
-
CD3 Complex / immunology*
-
CD4-Positive T-Lymphocytes / immunology
-
Clonal Anergy / genetics
-
Clonal Anergy / immunology
-
Graft Survival / genetics
-
Graft Survival / immunology
-
Heart Transplantation / immunology
-
Heart Transplantation / pathology
-
Immunosuppressive Agents / administration & dosage*
-
Lymphocyte Depletion
-
Membrane Glycoproteins / metabolism
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
Proto-Oncogene Proteins c-bcl-2 / biosynthesis
-
Proto-Oncogene Proteins c-bcl-2 / deficiency
-
Proto-Oncogene Proteins c-bcl-2 / genetics
-
bcl-X Protein
-
fas Receptor / physiology
Substances
-
Antibodies, Monoclonal
-
Antigens, CD
-
B7-1 Antigen
-
B7-2 Antigen
-
Bcl2l1 protein, mouse
-
CD28 Antigens
-
CD3 Complex
-
Cd86 protein, mouse
-
Immunosuppressive Agents
-
Membrane Glycoproteins
-
Proto-Oncogene Proteins c-bcl-2
-
bcl-X Protein
-
fas Receptor