title: The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity.
abstract: Inducible costimulatory molecule (ICOS) plays a pivotal role in T cell activation and Th1/Th2 differentiation. ICOS blockade has disparate effects on immune responses depending on the timing of blockade. Its role in transplantation immunity, however, remains incompletely defined. We used a vascularized mouse cardiac allograft model to explore the role of ICOS signaling at different time points after transplantation, targeting immune initiation (early blockade) or the immune effector phase (delayed blockade). In major histocompatibility-mismatched recipients, ICOS blockade prolonged allograft survival using both protocols but did so more effectively in the delayed-treatment group. By contrast, in minor histocompatibility-mismatched recipients, early blockade accelerated rejection and delayed blockade prolonged graft survival. Alloreactive CD4+ T cell expansion and alloantibody production were suppressed in both treatment groups, whereas only delayed blockade resulted in suppression of effector CD8+ T cell generation. After delayed ICOS blockade, there was a diminished frequency of allospecific IL-10-producing cells and an increased frequency of both IFN-gamma- and IL-4-producing cells. The beneficial effects of ICOS blockade in regulating allograft rejection were seen in the absence of CD28 costimulation but required CD8+ cells, cytotoxic T lymphocyte antigen-4, and an intact signal transducer and activator of transcription-6 pathway. These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo.
authors.affiliation: Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Atsushi
authors.initials: A
authors.lastname: Izawa
authors.forename: Sigrid E
authors.initials: SE
authors.lastname: Sandner
authors.forename: Toshiro
authors.initials: T
authors.lastname: Ito
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000818:Animals; D017209:Apoptosis; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection; D060945:Inducible T-Cell Co-Stimulator Ligand; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma