CD8 T cell response to vaccinia following lymphopenia

描述（由申请人提供）：本提案的重点是T细胞的稳态增殖如何影响它们产生抗病毒反应的能力。稳态增殖是成熟的幼稚T细胞在T细胞免疫缺陷时进行细胞分裂并明显转化为记忆细胞（“伪记忆”T细胞）的一种机制。虽然这一过程在孤立的情况下得到了很好的研究，但它对能够对感染因子作出反应的记忆细胞的产生和维持的影响尚未得到研究。在这里，我们将研究CD8 T细胞对牛痘（一种仍被用作天花疫苗的痘病毒）的反应如何受到稳态增殖的影响。这些伪记忆T细胞的抗病毒反应将与幼稚T细胞和真正的或“真正的”记忆T细胞进行比较，我们将通过故意接种疫苗产生记忆T细胞。使用TCR转基因T细胞将使我们能够比较这些不同分化状态下的T细胞群，但在每个群体中保持相同的TCR。有三个具体目标。在目标1中，我们将确定经过稳态增殖的TCR转基因T细胞（伪记忆T细胞）是否与真正的记忆T细胞有相似或不同的反应。这将包括测量T细胞的存活、维持、病毒感染的刺激和促进病毒清除的能力。在Aim #2中，我们将讨论伪记忆T细胞的维持和/或反应性是否可以通过接种疫苗来增强（或削弱）。最后，在Aim #3中，我们将逆转实验系统，并询问真正的记忆T细胞是否能够参与稳态增殖，以及这些细胞是否保持其功能特性。

DESCRIPTION (provided by applicant): This proposal focuses on how homeostatic proliferation of T cells influences their capacity to make an anti-viral response. Homeostatic proliferation is a mechanism through which mature naive T cells undergo cell division and apparent conversion to memory cells ("pseudo-memory" T cells) in response to T cell immunodeficiency. While this process is well studied in isolation, its impact on the generation and maintenance of memory cells which can respond to infectious agents has not been studied. Here we will examine how CD8 T cell responses to Vaccinia, a pox virus still used as the vaccine for Small Pox, is influenced by homeostatic proliferation. The anti-viral response of these pseudo-memory T cells will be compared to both naive T cells and true or "bona fide" memory T cells which we will generate by deliberate vaccination. The use of TCR transgenic T cells will allow us to compare T cell populations in these various differentiation states, yet maintain the identical TCR on each population. There are three Specific Aims. In Aim #1, we will determine whether TCR transgenic T cells which have undergone homeostatic proliferation (pseudo-memory T cells) respond similarly or differently from bona fide memory T ceils. This will involve measurement of T cell survival, maintenance, stimulation by viral infection and ability to contribute to viral clearance. In Aim #2, we will address whether the maintenance and/or reactivity of pseudo-memory T cells can be enhanced (or impaired) by vaccination. Finally, in Aim #3, we will reverse the experimental system and ask whether bona fide memory T cells are able to participate in homeostatic proliferation and whether these ceils maintain their functional properties.