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-1b, Mls-2b) and recipient (CBA/J: Mls-1a, Mls-2a) 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, TCRhigh+ thymocytes. Phenotypic analysis of TCR V beta 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 V beta 3+ and V beta 6+ T cells in mice with GVHD but not in controls. Using retroviral-mediated gene transfer to tag mature T cells, these V beta 3+ and V beta 6+ T cells could be shown to be derived from donor bone marrow precursors. Thymocytes expressing V beta 3 and V beta 6 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.
Holländer
G A
GA
Division of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115.
Widmer
B
B
Burakoff
S J
SJ
D000818:Animals; D016026:Bone Marrow Transplantation; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D008808:Mice, Inbred CBA; D016747:Minor Lymphocyte Stimulatory Antigens / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D016747:Minor Lymphocyte Stimulatory Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta