Studies on characteristics of CD8 T cell response for minor histocompatibility antigen, H60 and role of myeloid cells in the development of t cell response

Abstract

The balance between immunity and tolerance is required to maintain immune homeostasis. Understanding how tolerance can be induced extrathymically has important implication for attempts to establish a nonresponsive state to allogeneic antigens borne on tissue grafts and for reestablishing self-tolerance in patients suffering from autoimmune disease. In this study, I investigated whether the induction of help-deficient CD8 T cell response for H60 could generate memory impairment of the H60-specific CD8 T cells and whether the memory impairment of CD8 T cell specific for H60, the most dominant minor H antigen, would influence the immune hierarchy of CD8 T cells specific for other minor H antigens. Helper-deficient CD8 T cells show reduced burst expansion and the tolerance of H60-specific CD8 T cells has rendered CD8 T cells specific for other minor H antigens to be tolerized as well, reducing the total intensity of allo-response induced after transplantation. To understand the thymic selection process for H60-specific CD8 T cells and control of the specific response, I investigated the effect of a single amino acid substitution in the H60 epitope on the composition of the TCR repertoire. These results demonstrated that some overlap in TCR usage between CD8 T cells responding to H60H vs. H60N stimulation, suggesting that the H60H epitope will be useful for understanding the selection process and control of CD8 T cells specific for H60. In the third part, I showed that differentiation of transplanted Lin- cells into myeloid-derived suppressor cells inflamed skin to be the basis of the alleviation of skin inflammation after Lin- cell transplantation. Taken together, these results provide insight for modeling therapeutic applications to control CD8 T cell response.