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-γ), 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 Vβ and Vα TCR gene expression. The vast majority of clones express Vβ8.5 (12/12) and Vα11 (11/12). Although a limited number was evaluated, the nonpathogenic clones have only a Vα 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 α- and β-chains. Evaluation of the specificity of these clones suggests that the functional interaction between the N- terminal flanking region of CLIP (defined by the amine acid sequence -KPVSP- ) and the V region of the TCR is critical, allowing effective target cell recognition and tissue destruction in syngeneic GVHD.