Homeostatic Regulation of T Lymphocytes

免疫系统通过一种活性的免疫调节剂来控制淋巴细胞的数量和激活状态。 稳态调节机制。在转移到淋巴细胞减少的条件下，T细胞经历 在转移到淋巴细胞中后，T细胞增殖以补偿淋巴细胞缺乏，而T细胞在转移到淋巴细胞中后保持静止。 淋巴细胞足够的宿主。如何诱导和调节这种增殖的基本机制并不清楚。 很好理解。我们先前已经证明了淋巴细胞减少性T细胞增殖的异质性。 条件：IL-7依赖性缓慢增殖和IL-7非依赖性快速增殖（称为 “内源性增殖”）。此外，发现内源性增殖与 分化为记忆表型细胞，这表明不同的机制似乎涉及 内源性增殖从初步研究中，我们发现：1）初始积累的T细胞， 内源性增殖主要在脾脏中发现，但在肠系膜淋巴结中没有发现; 2） 抗生素处理对肠道植物群内源性增殖影响不大; 幼稚T细胞主要受记忆T细胞的存在控制; 4）库复杂性，但不是全部 记忆T细胞的数量在限制内源性增殖中起关键作用; 5）记忆CD 4 T细胞 抑制初始CD 4和CD 8 T细胞的内源性增殖，而记忆性CD 8 T细胞仅 抑制初始CD 8 T细胞的内源性增殖; 6）记忆T细胞彼此竞争，不仅 以保持它们的库大小，而且最大化库的复杂性。我们假设内源性 由DC上表达的自身抗原触发的T细胞增殖产生了多种多样的免疫调节因子。 记忆T细胞这些记忆细胞改变DC功能，进一步调节随后的幼稚T细胞 增殖为了检验这一假设，提出了三个具体目标。目标1将决定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 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 实验有望为理解外周T细胞的稳态调节提供重要的见解。 细胞这些研究在临床上与建立避免淋巴细胞稳态失调的策略相关， 常用于自身免疫或治疗性免疫消融。 定义细胞凋亡对记忆细胞稳态的贡献。完成建议

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