title: Immune tolerance to self-major histocompatibility complex class II antigens after bone marrow transplantation: role of regulatory T cells.
abstract: The immune system undergoes rapid reconstitution after autologous or syngeneic bone marrow transplantation with the re-establishment of tolerance to self-antigens. Administration of drugs such as cyclosporine that inhibit thymic-dependent clonal deletion disrupts the reconstitution of the immune system. In the absence of a peripheral regulatory T cells eliminated by the preparative regimen, systemic autoimmunity with pathology similar to graft-versus-host disease often develops. Moreover, the resolution of autoaggression is dependent on the reconstitution of CD4+ regulatory T cells. This study examined the specificity and function of this regulatory population assessed ex vivo that plays a critical role in down-regulating the autoreactive T lymphocyte response in cyclosporine-induced syngeneic graft-versus-host disease. The results suggest that both the antigen-specific regulatory and pathogenic effector T cells recognize a common peptide antigen framework (CLIP, a peptide derived from the invariant chain) presented by major histocompatibility complex class II molecules. Analysis of the CD4+ T-cell compartment revealed two subsets of CLIP-reactive T cells that differentially require the N- and C-terminal flanking domain of this peptide. Regulatory function is associated with the cells that require the C-terminal flanking domain. This population expresses the Foxp3 nuclear transcription factor and plays a critical role in re-establishing tolerance to self-major histocompatibility complex class II antigens. In addition to suppressing the production of type 1 cytokines, these regulatory T cells can direct the apoptotic death of the pathogenic autoreactive lymphocytes. This study also suggests that the development of functional regulatory activity is an active response initiated by the presence of autoreactive lymphocytes that can present the target antigen (major histocompatibility complex class II CLIP) to the regulatory T cells. Moreover, this process can be mimicked by peptide antigen in the absence of the pathogenic effector lymphocytes leading to the development of functional regulatory T-cell activity.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland 21231, USA. adhess@jhmi.edu
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Thoburn
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016572:Cyclosporine / Q000627:therapeutic use / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D053222:Fas Ligand Protein; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000502:physiology; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011828:Radiation Chimera / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014185:Transplantation, Isogeneic / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D019014:fas Receptor; C045084:invariant chain; D016572:Cyclosporine