Mechanisms of immune homeostasis and regulation of intra

可塑性是脊椎动物免疫系统的标志，并允许宿主动员必要数量的效应细胞进入炎症部位。在健康宿主中，感染或炎症的解决及时地将免疫系统恢复到现状，并且维持免疫稳态对于预防过敏性和自身免疫性疾病的发展至关重要。免疫系统在持续的炎症反应过程中改变淋巴细胞相对数量的固有能力是免疫稳态调节机制的一个重要方面。在这项研究中，我们集中在这一重要研究领域的两个未解决的问题：（i）炎症细胞是如何定向到炎症部位的？我们正在解决这个问题，通过研究机制，调节T细胞浸润到视网膜在实验性自身免疫性葡萄膜炎或炎症引起的炎症细胞因子，如干扰素-g，IL-1或IL-7在转基因小鼠眼睛的靶向表达。这些研究已经确定了影响淋巴细胞迁移到眼睛中的关键炎症分子，它们包括趋化因子如CCR 7、RANTES/CCL 5、RANTES/CXCL 9、正调节转录因子如T-bet以及负调节因子如细胞因子信号传导抑制因子1（SOCS 1）和SOCS 3。(ii)在宿主免疫需要强大的Th 1或Th 2应答的情况下，通过什么机制指示或引导宿主免疫系统改变Th 1、Th 2和ThIL 17淋巴细胞的平衡，并允许T细胞库的快速动态变化？我们以前已经表明，由炎症细胞分泌的细胞因子在调节T细胞活化或分化中起着至关重要的作用，并且细胞因子活性受到SOCS蛋白的反馈调节。我们在这里表明，通过低Ag剂量延长初始T细胞的活化诱导高水平的SOCS 1和SOCS 3表达，低水平的细胞活化（CD 62 L高，CD 25低，CD 44低），降低的T细胞增殖潜力（低IL-2分泌）和Th 2细胞因子的上调表达。SOCS 1的表达增强也上调了CCR 7的转录，并促进T细胞迁移到淋巴组织中，这表明SOCS蛋白可能通过调节T细胞的活化和迁移能力在调节T细胞稳态中发挥重要作用。

Plasticity is the hallmark of the vertebrate immune system and allows the host to mobilize the requisite numbers of effector cells into inflammatory sites. In the healthy host resolution of infection or inflammation restores the immune system to status quo in a timely manner and the maintenance of immune homeostasis is critical in preventing the development of allergic and autoimmune diseases. The inherent ability of the immune system to alter relative amounts of lymphocytes during the course of an ongoing inflammatory response is an essential aspect of mechanisms that underlie immune homeostatic regulation. In this study we have focused on two unresolved questions in this important area of research: (i) how are inflammatory cells directed to the site of inflammation? We are addressing this issue by investigating mechanisms that regulate the infiltration of T cells into retina in experimental autoimmune uveitis or during inflammation caused by targeted expression of inflammatory cytokines such as, interferon-g, IL-1 or IL-7 in transgenic mouse eye. These studies have identified critical inflammatory molecules that influence lymphocyte migration into the eye and they include chemokines such as CCR7, RANTES/CCL5, MIG/CXCL9, positive regulatory transcription factors such as T-bet, as well as, negative regulators such as suppressors of cytokine signaling 1(SOCS1) and SOCS3. (ii) By what mechanisms is the host immune system instructed or guided to alter the balance of Th1, Th2 and ThIL17 lymphocytes and permit rapid dynamic changes in T-cell repertoire in situations where host immunity requires robust Th1 or Th2 responses? We have previously shown that cytokines secreted by inflammatory cells play crucial roles in regulating T-cell activation or differentiation and that cytokine activities are under feedback regulation by SOCS proteins. We show here that prolonged activation of naive T-cells by low Ag dose induces high levels of SOCS1 and SOCS3 expression, lower levels of cellular activation (CD62Lhigh, CD25low, CD44low), diminished T-cell proliferation potential (low IL-2 secretion) and up-regulated expression of Th2 cytokines. Enhanced expression of SOCS1 also up-regulates transcription of CCR7 and promotes migration of T cells into lymphoid tissues, suggesting that SOCS proteins may play important roles in regulating T-cell homeostasis by modulating their activation and migration capacity.