Characterization of the pathogenic autoreactive T cells in cyclosporine-induced syngeneic graft-versus-host disease

Administration of the immunosuppressive drug cyclosporine after syngeneic b one marrow transplantation paradoxically elicits a systemic autoimmune synd rome resembling graft-vs-host disease (GVHD), This syndrome, termed syngene ic GVHD, is associated with the development of CD8(+) cytolytic T lymphocyt es that promiscuously recognize NHC 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-terminial flanking re gion of CLIP for activation, while there is a minor subset of nonpathogenic T cells that require the C-terminal flanking region. The present studies s how that pathogenic T cells produce type 1 cytokines (IL-2; IFN-gamma), whi le the nonpathogenic clones produce type 2 cytokines (IL-4; IL-IO), Moreove r, the repertoire of the pathogenic T cells is highly conserved with respec t to V beta and V alpha TCR gene expression. The vast majority of clones ex press V beta 8.5 (12/12) and V alpha 11l (11/12). Although a limited number was evaluated, the nonpathogenic clones have only a V alpha restriction. S equence analysis of the pathogenic T cell clones reveals a marked heterogen eity in the complementarity-determining region 3 domain and differential J region gene expression for both TCR alpha- and beta-chains, Evaluation of t he specificity of these clones suggests that the functional interaction bet ween the N-terminal flanking region of CUP (defined by the amino acid seque nce -KPVSP-) and the V region of the TCR is critical, allowing effective ta rget cell recognition and tissue destruction in syngeneic GVHD.