We are focusing on two aspects of T cell immunology: Activation and Tolerance. Activation: 1) The Danger model suggests that distressd normal tissue cells send signals that activate resting antigen presenting cells (APCs), which in turn, present antigens and co-stimulatory signals to resting T cells. To find such danger signals, it would be necessary to obtain resting APCs, ideally dendritic cells, the best professional APCS of the immue system.. We have been studying various parameters in an effort to grow resting dendritic cells from prescursors in bone marrow and have found that certain concentrations of GMCSF and IL4 allow these cells to grow out over a period of 5-6 days. Using these cells, we have begun to look for danger signals. 2) According to the danger model, rejection of transplanted tissues occurs because of the damage associated with the surgery. This damage induces the transplanted cells to send danger signals that activate the local APCs to present their antigens in an immunogenic way. We postulated that, once a tissue has healed in, the danger signals will subside and no immune response wil occur. To test this, we have transplanted foreign tissues to nude mice, allowed them to heal, and then infused the mice with competent T cells or transplanted them with neonatal thymuses. We found that healed skin grafts were rejected if they carried allogeneic transplantatnion antigens, but they were not rejected if they differed only by the antigen H-Y. We postulate that the dendritic cells from the transplanted tissue remain active for a longer period than we had surmised and are now testing this. 3) Four years ago we showed that killer T cells require help from helper T cells. We have since been studying the mechanism by which such help is delivered. We have now found that the help seems to go through the APC, rather than directly from the helper to the killer. We found that dendritic cells that have been cultured overnight with a cloned T helper against H-Y are now able to stimulate CD8 killers directly. 4) T cells that develop in the absence of B cells are defective in that they cannot generate help for antibody responses. This is in contrast to other T cell functions, such as DTH, killing ability, cytokine production, tissue rejection and granuloma production, which are not affected by the lack of B cells. 5) Pregnant female mice are immunized by the male antigen carried by their fetuses. Therefore the fetus does not obligatorily suppress the immune response of the mother. Tolerance: 1) We have found that tissues that have been allowed to settle into a nude mouse do not induce rejection when the mouse is reconstituted with T cells (see above). In addition. If the tissues are left long enough, the mouse is tolerant and does not reject a second graft of the same type. Thus, tissues can induce tolerance in mature T cell populations. 2) An infusion of B cells induces tolerance to the antigens they present, provided that the responding T cells are naive. This tolerance is not due to contaminating stem cells in the B cell preparation, however it lasts longer than the average life span of a B cell. We presume that the tolerance is induced by the B cells and maintained by chimerism stemming from development of the stem cells. The tolerance lasts as long as the chimerism lasts and then wanes provided that the animals continue to produce T cells from the thymus. In the absence of a thymus, the tolerance continues.
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