T cell diversity in the induction of autoimmunity

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): The graft-versus-host-disease (GVHD) which complicates allogeneic bone marrow transplantation is characterized by organ damage including dermatitis, enteritis, and hepatitis. A majority of post-transplant patients also develop antibodies to self-antigens, including anti-dsDNA, which mimic those in systemic lupus erythematosus. The development of both manifestations requires CD4+ T cells; however, the specificity of the inciting T cells is largely unknown. We propose to utilize transgenic models to examine the CD4 cell-antigen presenting cell (APC) interactions which initiate murine GVHD. K14 mice are a model of abnormal thymic development in which CD4+ T cells are autoreactive due to a failure of negative selection. H2-DM-deficient thymi select autoreactive CD4+ cells on restricted class II-associated peptides. K14 CD4 cells induce anti-dsDNA antibodies in syngeneic hosts; H2-DM-deficient CD4+ do not. 2-2-3 mice carry transgenes for the TCR genes from a B6-reactive K14 T cell hybridoma, 2-2-3. Double transgenic 2-2-3/K14 mice spontaneously develop skin disease which histologically resembles cutaneous GVHI); however, 2-2-31K14 CD4+ cells cannot induce autoantibodies in syngeneic mice. Thus, cutaneous GVHD is induced by monoclonal T cells which interact with keratinocytes; whereas, the production of autoantibodies during GVHD requires the activation of a diverse repertoire of T cells. In Specific Aim I, we will ask why K14, H2-DM, and 2-2-3/K14 CD4 cells induce different spectrums of autoantibodies after transfer to syngeneic hosts. We will examine the localization, division, and cytokine production of transferred CD4+ cells and B cell activation and germinal center production. Specific Aim II will extend these studies to investigate anti-DNA Ab production during GVHD in a mouse transgenic for the heavy chain of an anti-DNA antibody. In Specific Aim III, the keratinocyte/CD4+ cell interactions required for cutaneous GVHD in 2-2-3/K14 mice will be dissected. Temporal requirement for hematopoietic APC, inflammatory cytokines, and MHC class II expression in skin will be determined. Finally, in Specific Aim IV, we will identify the peptide specificity of the autoreactive 2-2-3 CD4 cell response to APC and keratinocytes in GVHD. Understanding the requirements for T cell diversity and the interactions between "graft" T cells and host antigen presenting cells offers improved immunologic targets for preventing GVHD following bone marrow transplant.