Memory T Cells in Tumpr Immunity

点击翻译按钮获取中文摘要

T cells can survive hematopoietic stem/progenitor cell transplants (HSPCT) following non-ablative and ablative conditioning regimens, for example radioresistant T cells mediate resistance to hematopoietic grafts and infection. Recent findings suggest that memory T cells (TM) should survive more effectively vs. naive cells as a result of enhanced anti-apoptotic regulation in this subset and new preliminary findings in this proposal demonstrate survival and expansion of host TM post-transplant. The experiments in this project will address questions testing the hypothesis that CD8 TM pre-conditioning and/or infused at transplant will result in increased host T cell survival and enhanced antigen-specific immunity in the early (reconstituting) post- transplant immune compartment. Experiments will examine the survival, expansion and function of memory populations in the post-HSPCT recipient. To accomplish these studies we will utilize and compare transgenic (OT-I) and non-transgenic (HBO)antigen specific TM including in vitro derived populations as developed in Project 2. Experiments in aim I are directed to elucidating the transplant parameters including conditioning and T cell replete or depleted inoculum on host memory cell survival in transplant models designed to track these TMpopulations. The involvement of IL-15and IL-7 in the maintenance and expansion of TM will be examined using fusion proteins (Core B) and knock-out strains (Core D) and experiments will also examine the role of CD30-CD30L interaction by memory cells post-transplant together with Project! Studies in aim II will examine the capacity of memory cells present to be reactivated in the reconstituting host=s lymphoid compartment. Antigen delivery will be examined using syngeneic host APC and compared to syngeneic tumors transfected with surrogate antigen. The effectiveness of gp96-lg transfectants as an antigen delivery vehicle will be investigated together with Project 1 as well as IL-15 transfected tumor populations with Project 2. Functional evaluation of responses by reactivated TM will be carried out using immune analysis (Core C). Finally, studies in aim III are designed to examine the ability of memory populations to respond to tumor antigens post-HSPCT. Models will be examined in which recipients bearing tumors will be administered vaccines in attempts to augment anti-tumor responses in the early post-transplant period and collaborative studies with Project 3 will examine effects of B cell deficiency in these responses.