Mechanisms of immune homeostasis and regulation of intra

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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.