title: The ICOS molecule plays a crucial role in the development of mucosal tolerance.
abstract: The ICOS molecule stimulates production of the immunoregulatory cytokine IL-10, suggesting an important role for ICOS in controlling IL-10-producing regulatory T cells and peripheral T cell tolerance. In this study we investigate whether ICOS is required for development of oral, nasal, and high dose i.v. tolerance. Oral administration of encephalitogenic myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to ICOS-deficient (ICOS-/-) mice did not inhibit experimental autoimmune encephalomyelitis (EAE), T cell proliferation, or IFN-gamma production, in striking contrast to wild-type mice. Similarly, intranasal administration of MOG(35-55) before EAE induction suppressed EAE and T cell responses in wild-type, but not in ICOS-/-, mice. In contrast, ICOS-/- mice were as susceptible as wild-type mice to high dose tolerance. These results indicate that ICOS plays an essential and specific role in mucosal tolerance and that distinct costimulatory pathways differentially regulate different forms of peripheral tolerance. Surprisingly, CD4+ cells from MOG-fed wild-type and ICOS-/- mice could transfer suppression to wild-type recipients, indicating that functional regulatory CD4+ cells can develop in the absence of ICOS. However, CD4+ T cells from MOG-fed wild-type mice could not transfer suppression to ICOS-/- recipients, suggesting that ICOS may have a key role in controlling the effector functions of regulatory T cells. These results suggest that stimulating ICOS may provide an effective therapeutic approach for promoting mucosal tolerance.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katsuichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Cherry I
authors.initials: CI
authors.lastname: Kingsley
authors.forename: Xingmin
authors.initials: X
authors.lastname: Zhang
authors.forename: Claudia
authors.initials: C
authors.lastname: Jabs
authors.forename: Leonid
authors.initials: L
authors.lastname: Izikson
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D000281:Administration, Intranasal; D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein; D007275:Injections, Intravenous; D051379:Mice; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D006023:Glycoproteins; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)