Memory CD8 T Cell Survival and Function Following Experimental BMT

描述(由申请人提供)：T细胞可以在非消融性和消融性条件处理方案后的造血干细胞/祖细胞移植(HSPCT)中存活，例如，抗辐射的T细胞介导对造血移植物和感染的抵抗。最近的发现表明，记忆T细胞(TM)应该比幼稚细胞更有效地存活下来，因为这一亚群中的抗凋亡调节得到了加强，这项研究的新的初步发现证明了输注和内源性抗原特异性宿主TM移植后的存活和扩张。这个项目中的实验将解决一些问题，以检验现有的CDS TM预适应和移植时输注的TM将导致移植后早期(重建)免疫隔间中抗原特异性免疫增强的假设。实验将检测记忆群体的存活、扩展和功能，并将它们与HSPCT后受者的原始T细胞进行比较。为了完成这些研究，我们将利用和比较TCR转基因(OT-I)和非转基因(H60)抗原特异性TM，包括体外衍生记忆种群。AIM I的实验旨在阐明移植参数，包括调节和T细胞补充或耗尽接种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的维持和扩展中的作用将通过融合蛋白和敲除菌株进行检测，实验还将检测移植后记忆细胞CD30-CD30L相互作用的作用。在AIM II上的研究将检查在重组宿主的淋巴隔间中存在的重新激活的记忆细胞的能力。抗原传递将使用同基因宿主APC进行检查，并与转导替代抗原的同基因肿瘤进行比较。将研究gp96-LG转染体作为抗原输送载体的有效性，以及IL-15转染性肿瘤细胞的有效性。将使用免疫分析对重新激活的TM的反应进行功能评估。最后，AIM III的研究旨在检验HSPCT后记忆群体对肿瘤抗原的反应能力。将研究携带肿瘤的受者将接受疫苗接种的模型，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.