THYMIC SELECTION AND THYMIC MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-IIEXPRESSION ARE ABNORMAL IN MICE UNDERGOING GRAFT-VERSUS-HOST REACTIONS

The graft-vs.-host reaction (GVHR) results in damage to the epithelial and lymphoid compartments of the thymus and thus in abnormal maturati on and function of thymocytes in mice undergoing GVHR. In this report, the effects of GVHR on thymic T cell receptor (TCR) expression and us age have been investigated. GVHR was induced in unirradiated F1 hybrid mice by the intravenous transfer of parental lymphoid cells. Expressi on of the CD3/TCR complex on thymocyte subsets defined by CD4 and CD8 was studied by three-color flow cytometry. The level of CD3/TCR was de creased on CD4+CD8-, but not CD4-CD8+, mature thymocytes. The lack of upregulation of CD3/TCR on CD4 single-positive thymocytes, but not on their CD8+ counterparts, suggested an abnormality of class II major hi stocompatibility complex (MHC) expression in the thymuses of mice unde rgoing GVHR. Immunofluorescence staining of thymic frozen sections rev ealed that MHC class II expression was dramatically decreased in GVH-r eactive mice. GVHR-induced changes in positive and negative selection were evaluated by determining the incidence of specific Vbeta TCR segm ent usage in the thymus. In normal mice, thymocyte usage of any given Vbeta segment was highly consistent between individuals of the same st rain and age; however, a marked divergence in the incidence of TCR Vbe ta6hi and Vbeta8hi cells between GVH-reactive littermate mice was obse rved, suggesting that thymic positive selection had become disregulate d in these animals. Furthermore, negative selection was defective; the incidence of phenotypically self-reactive Vbeta6hi T cells was signif icantly greater in the thymuses of GVH-reactive mice bearing the endog enous superantigen Mls-1a than in untreated controls. Thus, mice under going GVHR showed defective TCR upregulation on CD4+CD8- thymocytes an d changes in TCR usage reflecting aberrant thymic selection, in conjun ction with decreased expression of MHC class II. Most abnormalities of TCR expression and usage on CD4+ thymocytes observed in GVH-reactive mice were analogous to those of class II knockout mice.