title: CD40 ligand (CD154) triggers a short-term CD4(+) T cell activation response that results in secretion of immunomodulatory cytokines and apoptosis.
abstract: Signals generated through CD28-B7 and CD40 ligand (CD40L)-CD40 interactions have been shown to be crucial for the induction of long-term allograft survivability. We have recently demonstrated that humanized anti-CD40L (hu5C8) prevents rejection of mismatched renal allografts in primates. To investigate potential mechanisms of CD40L-induced allograft acceptance, we coimmobilized hu5C8 with suboptimal amounts of anti-CD3 to stimulate CD4(+) T cells. We now report that anti-CD3/CD40L costimulation results in CD28-independent activation and subsequent deletion of resting T cells. Coligation of CD3 and CD40L increased expression of CD69, CD25, and CD54 on CD4(+) T cells. We also found that costimulation with anti-CD3/CD40L resulted in enhanced production of interleukin (IL)-10, interferon gamma, and tumor necrosis factor alpha but not IL-2 or IL-6. Interestingly, after several days, anti-CD3/CD40L-mediated activation was followed by apoptosis in a significant population of cells. Consistent with that observation, anti-CD3/CD40L did not enhance the antiapoptotic proteins Bcl-2 and Bcl-xL. Further, the addition of CD28 at 24 h failed to rescue those cells induced to die after costimulation with anti-CD3/CD40L. Together, these data suggest that the graft-sparing effect of hu5C8 in vivo may result in part from early and direct effects on CD4(+) T cells, including a vigorous induction of immunomodulatory cytokines and/or apoptosis of allograft-specific T cells.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases-Navy Transplantation and Autoimmunity Branch, Naval Medical Research Center, Bethesda, Maryland 20889-5607, USA. blairp@nmripo.nmri.nnmc.navy.mil
authors.forename: P J
authors.initials: PJ
authors.lastname: Blair
authors.forename: J L
authors.initials: JL
authors.lastname: Riley
authors.forename: D M
authors.initials: DM
authors.lastname: Harlan
authors.forename: R
authors.initials: R
authors.lastname: Abe
authors.forename: D K
authors.initials: DK
authors.lastname: Tadaki
authors.forename: S C
authors.initials: SC
authors.lastname: Hoffmann
authors.forename: L
authors.initials: L
authors.lastname: White
authors.forename: T
authors.initials: T
authors.lastname: Francomano
authors.forename: S J
authors.initials: SJ
authors.lastname: Perfetto
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
authors.forename: C H
authors.initials: CH
authors.lastname: June
mesh_terms: D015703:Antigens, CD / Q000032:analysis / Q000502:physiology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; D016207:Cytokines; D007074:Immunoglobulin G; D007378:Interleukins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D023201:CD40 Ligand; D007371:Interferon-gamma