Mechanisms of T cell immunosuppression during the graft-versus-host reaction

The studies presented in this thesis examine the mechanisms of T cell immunosuppression during the graft-versus-host reaction (GVHR). GVHR was induced by the injection of parental lymphoid cells into F1 hybrid recipient mice. The ensuing acute reaction consisted of an initial immunoproliferative phase, followed by the development of profound immunosuppression and histopathological lesions of epithelial and lymphoid tissues. Survivors of the acute reaction developed the persistent immune abnormalities characteristic of chronic GVHR.We have found that the T cell protein tyrosine kinases p56$ rm sp{lck}$ and p59$ rm sp{fyn}$, involved in signal transduction through the T cell receptor (TCR), are downregulated in the T cells of mice during GVHR. The reduction of lck and fyn was prevented by adrenalectomy of the recipients, and a similar reduction could be induced in normal (non-GVH-reactive) mice by an injection of exogenous cortisone. These findings suggested that the GVHR-induced elevation in endogenous glucocorticoid levels could trigger the decrease of T cell lck and fyn, resulting in a T cell signalling defect during GVHR. In fact, we have demonstrated that glucocorticoids induced a decrease in lck and fyn in T cell clones in vitro. Thus, it appeared that the early GVHR-induced T cell unresponsiveness was due to the glucocorticoid-dependent downregulation of T cell lck and fyn.We have investigated changes in T cell maturation and selection in the GVHR-dysplastic thymus, which may account for the persistent immune abnormalities of chronic GVHR. Thymocyte TCR expression and usage were aberrant during GVHR; changes included decreased expression of CD3 on CD4$ sp+$8 thymocytes, inconsistent TCR V$ beta$ usage, and appearance of phenotypically autoreactive mature thymocytes. These abnormalities, suggestive of defective positive and negative selection, are likely to result from the GVHR-induced decrease in thymic class II MHC expression. Altered T cell education may lead to the long-term peripheral T cell defects observed in chronic GVHR. Lastly, we report that GVHR-induced cutaneous injury was exacerbated by irradiation of the target tissue, suggesting that in clinical GVHR, irradiation may intensify tissue damage, including thymic epithelial lesions; this could potentially lead to more serious alterations in thymic function, and thus to longer lasting, more severe peripheral T cell immune deficiency