title: Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection.
abstract: Although induction of CD8 T-cell responses to transplants requires CD4-cell help, how this help is transmitted remains incompletely characterized. In vitro, cognate interactions between CD4 T cells and dendritic cells (DCs) induce C3a and C5a production. CD8(+) T cells lacking C3a receptor (C3aR) and C5a receptor (C5aR) proliferate weakly to allogeneic DCs despite CD4 help, indicating that CD4-cell help is mediated, in part, through DC-derived C3a/C5a acting on CD8(+) T cell-expressed C3aR/C5aR. In support of this concept, augmenting DC C5a/C3a production bypasses the requirement for CD4- and CD40-dependent help to wild-type CD8(+) T cells. CD4-deficient recipients of allogeneic heart transplants prime weak CD8 responses and do not acutely reject their grafts. In contrast, CD4-deficient chimeric mice possessing decay accelerating factor deficient (Daf1(-/-)) bone marrow, in which DC C3a/C5a production is potentiated, acutely reject transplants through a CD8 cell-dependent mechanism. Furthermore, hearts transplanted into CD40(-/-) mice prime weak CD8-cell responses and survive indefinitely, but hearts transplanted into Daf1(-/-)CD40(-/-) recipients undergo CD8 cell-dependent rejection. Together, the data indicate that heightened production and activation of immune cell-derived complement bypasses the need for CD40/CD154 interactions and implicate antigen-presenting cell-produced C5a and C3a as molecular bridges linking CD4 help to CD8(+) T cells.
authors.affiliation: Renal Division, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Vieyra
authors.forename: Staci
authors.initials: S
authors.lastname: Leisman
authors.forename: Hugo
authors.initials: H
authors.lastname: Raedler
authors.forename: Wing-Hong
authors.initials: WH
authors.lastname: Kwan
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Strainic
authors.forename: M Edward
authors.initials: ME
authors.lastname: Medof
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002478:Cells, Cultured; D015926:Complement C3a / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006084:Graft Rejection; D016027:Heart Transplantation / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand; D015926:Complement C3a; D015936:Complement C5a; D003165:Complement System Proteins