Characterization of the pathogenic autoreactive T cells in cyclosporine-induced syngeneic graft-versus-host disease.
Administration of the immunosuppressive drug cyclosporine after syngeneic bone marrow transplantation paradoxically elicits a systemic autoimmune syndrome resembling graft-vs-host disease (GVHD). This syndrome, termed syngeneic GVHD, is associated with the development of CD8+ cytolytic T lymphocytes that promiscuously recognize MHC class II molecules in association with a peptide from the invariant chain (CLIP). Clonal analysis reveals a major subset of cells that are pathogenic and require the N-terminal flanking region of CLIP for activation, while there is a minor subset of nonpathogenic T cells that require the C-terminal flanking region. The present studies show that pathogenic T cells produce type 1 cytokines (IL-2; IFN-gamma), while the nonpathogenic clones produce type 2 cytokines (IL-4; IL-10). Moreover, the repertoire of the pathogenic T cells is highly conserved with respect to V beta and V alpha TCR gene expression. The vast majority of clones express V beta8.5 (12/12) and V alpha11 (11/12). Although a limited number was evaluated, the nonpathogenic clones have only a V alpha restriction. Sequence analysis of the pathogenic T cell clones reveals a marked heterogeneity in the complementarity-determining region 3 domain and differential J region gene expression for both TCR alpha- and beta-chains. Evaluation of the specificity of these clones suggests that the functional interaction between the N-terminal flanking region of CLIP (defined by the amino acid sequence -KPVSP-) and the V region of the TCR is critical, allowing effective target cell recognition and tissue destruction in syngeneic GVHD.
Chen
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W
Division of Immunology and Hematopoiesis, Oncology Center, Johns Hopkins University, Baltimore, MD 21287-8985, USA.
Thoburn
C
C
Hess
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AD
D000595:Amino Acid Sequence; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015551:Autoimmunity; D016026:Bone Marrow Transplantation; D016572:Cyclosporine / Q000009:adverse effects*; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006086:Graft vs Host Disease / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D006649:Histocompatibility Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D051381:Rats; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000944:Antigens, Differentiation, B-Lymphocyte; D006649:Histocompatibility Antigens; D000949:Histocompatibility Antigens Class II; D007378:Interleukins; D008222:Lymphokines; D016693:Receptors, Antigen, T-Cell, alpha-beta; C038353:histocompatibility antigens RT, rat; C045084:invariant chain; D007371:Interferon-gamma; D016572:Cyclosporine