Homeostatic Regulation of T Lymphocytes

描述(申请人提供)：免疫系统通过调节体内平衡的主动机制来控制淋巴细胞的数量和激活状态。T细胞进入淋巴细胞缺乏状态后，T细胞进行增殖以弥补淋巴细胞不足，而T细胞在进入淋巴细胞充足的宿主后保持静止。关于这种扩散是如何被诱导和调控的潜在机制还不是很清楚。我们以前已经证明了T细胞在淋巴细胞减少的条件下增殖的异质性：依赖IL-7的慢增殖和不依赖IL-7的快速增殖(称为内源性增殖)。此外，内源性增殖与分化为记忆表型细胞密切相关，提示内源性增殖可能涉及不同的机制。通过初步研究，我们发现：1)内源性T细胞的初始积聚主要在脾内，而不是在肠系膜淋巴结中；2)抗生素治疗耗尽肠道菌群对内源性增殖影响不大；3)初始T细胞的内源性增殖主要受记忆T细胞的存在控制；4)记忆T细胞的种类复杂性而不是总数在限制内源性增殖中起关键作用；5)记忆CD4 T细胞抑制初始CD4和CD8 T细胞的内源性增殖，而记忆CD8 T细胞仅抑制初始CD8 T细胞的内源性增殖；6)内存T细胞相互竞争，不仅是为了保持池的大小，而且还为了最大限度地提高曲目的复杂性。我们假设，树突状细胞上表达的自身抗原触发的内源性T细胞增殖产生了一系列不同的记忆T细胞。这些记忆细胞改变DC功能，进一步调节随后的初始T细胞增殖。为了检验这一假说，本文提出了三个具体目标。目的#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。目的#2将确定记忆T细胞抑制初始T细胞内源性增殖的细胞机制。目标#3将确定细胞凋亡对记忆细胞稳态的贡献。这些研究对建立避免淋巴细胞稳态失调的策略具有临床意义，淋巴细胞稳态失调常见于自身免疫或治疗性免疫消融。公共卫生相关性：免疫系统进化出一种主动的动态平衡控制机制，以确保其多样性和功能性。动态平衡失调被认为与多种疾病的发展有关，包括免疫缺陷、自身免疫和实体器官移植失败。目前的建议旨在研究潜在的细胞机制，结果将有助于我们理解免疫机制，并促进治疗策略，以治疗由调节失调引起的疾病。

DESCRIPTION (provided by applicant): 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 define the contribution of apoptosis to memory cell homeostasis. The studies are clinically relevant to establish strategies to avoid dysregulated lymphocyte homeostasis, often found in autoimmunity or therapeutic immunoablation. PUBLIC HEALTH RELEVANCE: The immune system evolves an active process of homeostatic control mechanism that ensures its diversity and functionality. Homeostatic dysregulation is believed to link to the development of multiple disorders, including immunodeficiency, autoimmunity and a failure of solid organ transplantation. The current proposal aims to investigate underlying cellular mechanism, and the results will aid our understanding of the immune mechanism and facilitate therapeutic strategies to treat disorders caused by the dysregulation.