Homeostatic Regulation of T Lymphocytes

描述（由申请人提供）：免疫系统通过一种主动的稳态调节机制控制淋巴细胞的数量和激活状态。转移到淋巴细胞减少状态后，T细胞进行增殖以补偿淋巴细胞缺乏，而T细胞在转移到淋巴细胞充足宿主后保持静止。这种增殖如何被诱导和调控的潜在机制尚不清楚。我们之前已经证明了淋巴细胞减少条件下T细胞增殖的异质性：依赖il -7的缓慢增殖和不依赖il -7的快速增殖（称为“内源性增殖”）。此外，发现内源性增殖与向记忆表型细胞的分化密切相关，表明内源性增殖可能涉及不同的机制。从初步研究中我们发现：1)T细胞的初始积累主要发生在脾脏，而不是肠系膜淋巴结；2)抗生素对肠道菌群的消耗对内源性增殖影响不大；3)幼稚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细胞库的复杂性而非总数在限制内源性T细胞增殖中起关键作用；5)记忆性CD4 T细胞同时抑制原生CD4和CD8 T细胞的内源性增殖，而记忆性CD8 T细胞仅抑制原生CD8 T细胞的内源性增殖；6)记忆T细胞相互竞争，不仅要维持它们的池大小，而且要最大限度地提高库的复杂性。我们假设内源性T细胞增殖，由dc上表达的自身抗原触发，产生多种记忆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。为了检验这一假设，提出了三个具体目标。目的1将确定dc是否需要在淋巴细胞减少的宿主中诱导内源性增殖。目的2将定义介导记忆T细胞抑制幼稚T细胞内源性增殖的细胞机制。目的3将定义细胞凋亡对记忆细胞稳态的贡献。这些研究具有临床意义，有助于建立避免自身免疫或治疗性免疫消融术中常见的淋巴细胞稳态失调的策略。公共卫生相关性：免疫系统进化为一种主动的自我平衡控制机制，以确保其多样性和功能性。体内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。本研究旨在探讨其潜在的细胞机制，其结果将有助于我们对免疫机制的理解，并为治疗由失调引起的疾病提供治疗策略。

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.