title: CD8+ T cells negatively regulate IL-4-dependent, IgG1-dominant posttransplant alloantibody production.
abstract: We have previously reported that CD8(+) T cells significantly influence Ab production based on the observation that posttransplant alloantibody levels in CD8-deficient murine hepatocyte transplant recipients are markedly enhanced. However, the precise mechanisms contributing to enhanced alloantibody production in the absence of CD8(+) T cells is not understood. We hypothesized that alloactivated CD8(+) T cells inhibit Ab production by skewing toward a proinflammatory cytokine profile, whereas when these cells are absent, an anti-inflammatory cytokine profile shifts the alloimmune response toward alloantibody production. To investigate this possibility, alloantibody isotype profiles were examined in CD8-deficient and wild-type hepatocyte recipients. We found that IgG1 (IL-4-dependent isotype) was the dominant alloantibody isotype in wild-type recipients as well as in CD8-deficient recipients, although the amount of alloantibody in the latter group was substantially higher. Utilizing real-time PCR we found that CD4(+) T cells from wild-type recipients significantly upregulated IFN-γ but not IL-4 mRNA. In contrast, in the absence of CD8(+) T cells, CD4(+) T cells switched to significantly upregulate IL-4 mRNA, while IFN-γ was downregulated. IL-4 knockout mice do not produce any posttransplant alloantibody. However, adoptive transfer of wild-type CD4(+) T cells into CD8-depleted IL-4 knockout mice restores high alloantibody levels observed in CD8-depleted wild-type recipients. This suggests that IL-4-producing CD4(+) T cells are critical for posttransplant alloantibody production. Additionally, this CD8-mediated regulation of posttransplant alloantibody production is IFN-γ-dependent. Further elucidation of the mechanisms by which CD8(+) T cells influence Ab production will significantly contribute to development of therapies to manipulate humoral responses to Ag.
authors.affiliation: Department of Surgery, Comprehensive Transplant Center, Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Zimmerer
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Pham
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Sanders
authors.forename: Ginny L
authors.initials: GL
authors.lastname: Bumgardner
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000637:transplantation*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D007518:Isoantibodies / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D007518:Isoantibodies; D015847:Interleukin-4; D007371:Interferon-gamma