Memory CD8 T Cell Survival and Function Following Experimental BMT

描述（由申请人提供）：T细胞可以在非消融和消融治疗方案下存活于造血干细胞/祖细胞移植（HSPCT），例如耐辐射T细胞介导对造血移植和感染的抵抗。最近的研究结果表明，记忆T细胞（TM）应该比原始细胞更有效地存活，因为这一亚群的抗凋亡调节增强了，本提案的新初步研究结果表明，输注和内源性抗原特异性宿主TM移植后存活和扩增。本项目的实验将解决以下假设的问题：现有的CDS TM预处理和移植时注入的TM将导致移植后早期（重建）免疫区抗原特异性免疫增强。实验将检查记忆细胞群的存活、扩增和功能，并将它们与hspct后受体的幼稚T细胞进行比较。为了完成这些研究，我们将利用并比较TCR转基因（OT-I）和非转基因（H60）抗原特异性TM，包括体外来源的记忆群体。目的1的实验旨在阐明移植参数，包括条件调节和T细胞充满或耗尽接种量对宿主记忆细胞存活的影响，这些模型旨在跟踪这些TM群体。IL-15和IL-7在TM维持和扩增中的作用将通过融合蛋白和敲除菌株进行研究，实验还将研究移植后记忆细胞中CD30-CD30L相互作用的作用。目的II的研究将检查记忆细胞在重建宿主淋巴细胞室中被重新激活的能力。抗原递送将使用同源宿主APC进行检测，并与转染了替代抗原的同源肿瘤进行比较。gp96-lg作为抗原递送载体的有效性以及IL-15转染的肿瘤群体将被研究。通过免疫分析对重新激活的TM反应进行功能评估。最后，aim III的研究旨在检查记忆群体对hspct后肿瘤抗原的反应能力。将检查模型，其中携带肿瘤的受者将接种疫苗，试图在移植后早期增强抗肿瘤反应。

DESCRIPTION (provided by applicant): 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 infused and endogenous antigen specific host TM post-transplant. The experiments in this project will address questions testing the hypothesis that existing CDS TM pre-conditioning and TM infused at the time of transplant will result in enhanced antigen-specific immunity in the early (reconstituting) post-transplant immune compartment. Experiments will examine the survival, expansion and function of memory populations and compare them to naive T cells in the post-HSPCT recipient. To accomplish these studies we will utilize and compare TCR transgenic (OT-I) and non-transgenic (H60) antigen specific TM including in vitro derived memory populations. 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 models designed to track these TM populations. The involvement of IL-15 and IL-7 in the maintenance and expansion of TM will be examined using fusion proteins and knock-out strains and experiments will also examine the role of CD30-CD30L interaction by memory cells post-transplant. 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 as well as IL-15 transfected tumor populations. Functional evaluation of responses by reactivated TM will be carried out using immune analyses. 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.