Homeostatic Regulation of T Lymphocytes

免疫系统控制淋巴细胞的数量和激活状态，通过激活的 动态平衡调节机制。在转移到淋巴细胞减少的情况下，T细胞经历 增殖以弥补淋巴细胞不足，而T细胞在转移到 淋巴细胞充足的宿主。这种增殖如何被诱导和调控的潜在机制并不是 很好理解。我们先前已经证明在淋巴细胞减少的情况下T细胞增殖的异质性。 条件：IL-7依赖的慢增殖和IL-7非依赖的快速增殖(简称 “内源扩散”)。此外，还发现内源性增殖与 分化为记忆表型细胞，表明不同的机制似乎参与了 内源性增殖。从初步研究中我们发现：1)T细胞在经历了 内源性增殖主要见于脾，但不存在于肠系膜淋巴结；2)耗竭 抗生素处理的肠道菌群对内源性增殖影响不大；3)内源性增殖 原始T细胞主要受记忆T细胞的存在控制；4)谱系的复杂性但不是全部 记忆性T细胞的数量在限制内源性增殖中起关键作用；5)记忆性CD4T细胞 抑制初始CD4和CD8 T细胞的内源性增殖，而只抑制记忆性CD8 T细胞 抑制幼稚CD8 T细胞的内源性增殖；6)记忆T细胞相互竞争，不仅 以保持其池的大小，但也最大限度地增加曲目的复杂性。我们假设内生性 树突状细胞上表达的自身抗原引发的T细胞增殖产生了不同的 记忆T细胞。这些记忆细胞改变了DC的功能，进一步调节了后续的初始T细胞 扩散。为了检验这一假说，本文提出了三个具体目标。目标1将确定DC是否 是诱导淋巴细胞减少宿主内源性增殖所必需的。目标2将定义 记忆T细胞抑制幼稚T细胞内源性增殖的细胞机制。目标 #3将 实验有望为理解外周T细胞的动态平衡调节提供重要的见解 细胞。这些研究对建立避免淋巴细胞内稳态失调的策略具有临床意义。 常见于自身免疫或治疗性免疫消融。 明确细胞凋亡对记忆细胞动态平衡的贡献。完成拟议的

The immune system controls the numbers as well as the activation status of the lymphocytes by an active mechanism of homeostatic regulation. Following transfer into lymphopenic conditions, T cells undergo proliferation to compensate lymphocyte deficiency, while T cells remain quiescent after transfer into lymphocyte sufficient hosts. Underlying mechanisms of how such proliferation is induced and regulated are not well understood. We have previously demonstrated heterogeneity of T cell proliferation under lymphopenic conditions: IL-7-dependent slow proliferation and IL-7-independent fast proliferation (referred to as "endogenous proliferation"). Furthermore, endogenous proliferation is found closely associated with differentiation into memory phenotype cells, suggesting that different mechanism appears to be involved in endogenous proliferation. From preliminary studies we found that: 1) initial accumulation of T cells that undergo endogenous proliferation is found mainly in the spleen but not in the mesenteric lymph nodes; 2) depletion of gut flora by antibiotic treatment has little effect on endogenous proliferation; 3) endogenous proliferation of naive T cells is mainly controlled by the presence of memory T cells; 4) repertoire complexity but not total numbers of the memory T cells plays a key role in limiting the endogenous proliferation; 5) memory CD4 T cells suppress endogenous proliferation of both naive CD4 and CD8 T cells, while memory CD8 T cells only suppress endogenous proliferation of naive CD8 T cells; 6) memory T cells compete with each other, not only to maintain their pool size but also to maximize the repertoire complexity. We hypothesize that endogenous T cell proliferation, triggered by self-antigens expressed on DCs generates a diverse repertoire of memory T cells. These memory cells alter DC functions, further regulating subsequent naive T cell proliferation. Three specific aims are proposed in order to test the hypothesis. Aim #1 will determine if DCs are required for the induction of endogenous proliferation in lymphopenic hosts. Aim #2 will define cellular mechanisms mediating memory T cell inhibition of naive T cell endogenous proliferation. Aim #3 will experiments is expected to provide important insights into understanding homeostatic regulation of peripheral T cells. The studies are clinically relevant to establish strategies to avoid dysregulated lymphocyte homeostasis, often found in autoimmunity or therapeutic immunoablation. define the contribution of apoptosis to memory cell homeostasis. Completion of the proposed