Loss of normal thymic repertoire selection and persistence of autoreactive T cells in graft vs host disease

To assess the influence of graft vs host disease (GVHD) on T cell development and thymic repertoire selection, a murine transplantation model was chosen, in which donor (B10.BR: Mls-1^b, Mls-2^b) and recipient (CBA/J:Mls-1^a, Mls-2^a) mice differ in their minor lymphocyte-stimulating Ag. Mature splenic T cells of donor origin were added to the T cell-depleted bone marrow cells to induce moderate GVHD. When analyzed 5 and 10 wk after transplantation, animals with GVHD, but not disease-free controls, demonstrated aberrant thymic maturation with an increase in single positive, TCR(high +) thymocytes. Phenotypic analysis of TCR Vβ expression in mature thymocytes and peripheral T cells revealed a disruption of negative thymic selection of Mls-reactive T cells with the subsequent emergence of Vβ3⁺ and Vβ6⁺ T cells in mice with GVHD but not in controls. Using retroviral- mediated gene transfer to tag mature T cells, these Vβ3^- and Vβ6⁺ T cells could be shown to be derived from donor bone marrow precursors. Thymocytes expressing Vβ3 and Vβ6 were efficiently activated upon cross-linking of their TCRs and peripheral T cells from mice with GVHD proliferated to host- derived splenocytes in a MLR. When transferred to sublethally irradiated CBA/J recipients, only T cells from mice with GVHD expanded dramatically. These data suggest that the lack of proper thymic selection after bone marrow transplantation results in the survival and persistence of self-reactive T cells, which might be responsible for the autoimmune manifestations of chronic GVHD.