title: IFN-γ production by memory helper T cells is required for CD40-independent alloantibody responses.
abstract: Cognate T-B cell interactions and CD40-CD154 costimulation are essential for productive humoral immunity against T-dependent Ags. We reported that memory CD4 T cells can deliver help to B cells and induce pathogenic IgG alloantibodies in the absence of CD40-CD154 interactions. To determine cytokine requirements for CD40-independent help, we used CD40(-/-) mice containing differentiated subsets of donor-reactive memory Th cells as heart allograft recipients. Th1 and Th17, but not Th2, memory CD4 T cells elicited high titers of anti-donor Ab. Abs induced by Th17 memory CD4 T cells had decreased reactivity against donor MHC class I molecules and inferior ability to cause complement deposition in heart allografts compared with Abs induced by Th1 cells, suggesting a requirement for IFN-γ during CD40-independent help. IFN-γ neutralization inhibited helper functions of memory CD4 T cells in both CD40(-/-) recipients and wild type recipients treated with anti-CD154 mAb. Our results suggest that IFN-γ secreted by pre-existing memory helper cells determines both isotype and specificity of donor-reactive alloantibodies and can thus affect allograft pathology. This information may be valuable for identifying transplant patients at risk for de novo development of pathogenic alloantibodies and for preventing alloantibody production in T cell-sensitized recipients.
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195; and Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gorbacheva
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195; and Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Ran
authors.initials: R
authors.lastname: Fan
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195; and Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195; and Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195; and Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195; and Department of Immunology, Cleveland Clinic, Cleveland, OH 44195 valujsa@ccf.org.
authors.forename: Anna
authors.initials: A
authors.lastname: Valujskikh
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002454:Cell Differentiation; D003165:Complement System Proteins / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D056724:Immunity, Humoral; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis*; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014019:Tissue Donors; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D019013:CD40 Antigens; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D007371:Interferon-gamma; D003165:Complement System Proteins