This project addresses the development of primary cytolytic T lymphocytes [CTL] in the human system. CTL are antigen-specific and constitute one of several important host resistance mechanisms. They have also been implicated in the converse problems of graft rejection and graft-vs-host disease in allogeneic bone marrow transplantation. While many studies have examined the effector function of CTL from cell lines or polyclonal mitogen stimulated cultures, there remain important unknowns. Specifically, what accessory or antigen-presenting cells [APC] are need, and what cytokines are utilized in the development of Ag-specific, class I MHC restricted, primary CTL in the human? Dendritic cells constitute a trace subpopulation of blood leukocytes, but they have potent stimulatory properties for primary T cell responses. Accordingly, the biology of primary CTL development will be studied in the allogeneic mixed leukocyte reaction, using dendritic cells in comparison with other candidate APCs. Specifically, how do potential APCs bind resting CD8+ T cells and sensitize CTL precursors to MHC antigens in the allogeneic MLR? Responding lymphocytes bind to active APCs in stable clusters and can be physically separated from nonresponding lymphocytes. Alloantigen-specific CD8+ cells can also be cloned from single cell precursors using defined APC populations and crude cytokine supernatant. Using these tools, the developing CTL requirements for continued Ag presence and specific cytokines will be explored. The ability to clone such CTL form both unprimed single precursors, and from sensitized cluster-derived T cells, will provide a rigorous means of studying the cellular and cytokine requirements for the early responses of primary CTL. An improved understanding of primary CTL generation, including responses to human minor histocompatibility differences, should help elucidate cellular mechanisms responsible for GvHD and graft rejection, and might suggest strategies for their prevention in allogeneic bone marrow transplantation.
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| Young, J W; Steinman, R M (1990) Dendritic cells stimulate primary human cytolytic lymphocyte responses in the absence of CD4+ helper T cells. J Exp Med 171:1315-32 |
