This project explored the fate of the T cell mediated memory response in vivo following manipulations that induce apoptosis of T memory cells. FVB (H-2q) mice were primed to an MHC class I Dd alloantigen by skin graft or spleen cell immunization with cells from FVB transgenics expressing Dd ubiquitously (MHC-Dd). Primed mice exhibit accelerated rejection of subsequently placed Dd skin grafts with a median survival time (MST) of 8 days (n=29) compared to the primary response of 12 days (n=57), demonstrating T cell mediated memory. Sub-lethal irradiation (550 R) of mice so primed obliterated the memory response and induced prolonged survival of Dd skin grafts (MST=24.5 days, n=10). To asssess the effects of antigen presentation on the fate of the memory response following sub-lethal irradiation, irradiated primed mice were infused with Dd expressing bone marrow cell (BMC) populations that differed in antigen presenting capacity: MHC-Dd BMC were used as a source of immunostimulatory APC because the antigen is expressed on all cells, including dendritic cells, and primes FVB mice to Dd; CD2-Dd BMC, originating in FVB transgenics in which Dd is regulated by the CD2 promoter, were used as a source of non-stimulatory APC because Dd is expressed solely on B cells, which are tolerogenic. Infusion of immunostimulatory MHC-Dd BMC into irradiated mice preserved the accelerated rejection response of Dd skin grafts (MST=8,n=9), mediated by T memory cells, whereas infusion of non-stimulatory APC not only failed to preserve accelerated rejection, but in fact, induced antigen specfic tolerance to Dd skin grafts(MST>111, n=15). The mechanism of tolerance in this system does not depend on induction of anergy or clonal deletion of Dd specific T cells, but rather appears to depend on the presence of Dd specific antibody and establishment of thymic chimerism with Dd expressing lymphocytes. Because many Dd expressing cells in the thymus of tolerant mice are coated by antibody, and such cells are not detectable in the periphery, tolerance in this system may be mediated mechanically, by opsonization of Dd expressing cells to which are bound both Dd specific antibody and Dd specific T cells, i.e., by antigen reactive cell opsonization (ARCO). Thus tolerance in these mice may rather reflect a form of immune """"""""diversion"""""""" rather than a truly tolerant state. The fate of the T memory cells themselves following irradiation or other insults, and subsequent antigen presentation is the thrust of future studies.
