Chemokines and regulation of T cell responses during infection

趋化因子调节各种免疫效应细胞的运输和功能，在宿主免疫中起着重要作用。 防御多种细胞内病原体。CXC趋化因子受体3（CXCR 3）在 浆细胞样树突细胞、嗜中性粒细胞、自然杀伤（NK）细胞和T细胞。CXCR 3配体（CXCR 3Ls）， 特别是CXCL 9（Mig）和CXCL 10（IP-10）在利什曼原虫感染期间以高水平产生，但它们的 在介导抗利什曼病的保护性免疫中的作用尚不清楚。我们之前已经证明， CXCR 3在介导抗皮肤李斯特菌的免疫中起关键作用。耐药C57 BL/6小鼠的主要感染 通过控制募集的CD 4+和CD 8 + T细胞感染的皮肤和IFN-？在病变内产生。 我们还发现，CXCR 3在相当大比例的记忆T细胞上表达，并且是记忆T细胞所必需的。 它们在再激发后迁移到真皮。我们的初步研究表明，L.主要易感的 BALB/c小鼠，而不是抗性C57 BL/6小鼠，在活化后不能上调CXCR 3，尽管CXCR 3在小鼠体内表达。 产生相当水平的干扰素-？C57 BL/6 T细胞。我们最近的研究表明， CXCR 3在CD 4+和CD 8 + T细胞上的表达是通过多种机制控制的。我们还发现 B7共刺激通路参与维持和调节L. 主要抗性小鼠。这些发现使我们推测CXCR 3调节宿主对L. 主要通过控制寄生虫特异性效应子和记忆T细胞反应，BALB/c小鼠具有 上调T细胞上CXCR 3的缺陷，这有助于它们对L.少校这个的目标 建议评估CXCR 3在调节利什曼特异性效应和记忆T细胞中的作用， 在L.主要感染，并确定如何控制CXCR 3表达的T细胞。(Aim第一章 将研究CXCR 3在调节抗原特异性效应CD 4+和CD 8 + T细胞应答中的作用 在初级L.耐药C57 BL/6小鼠中的主要感染。（目标2）将决定CXCR 3在 调节记忆T细胞的募集和功能。C57 BL/6小鼠中的主要感染。(Aim（3）意志 确定CXCR 3在CD 4+和CD 8 + T细胞上表达上调的机制， C57 BL/6小鼠，并将阐明参与预防CXCR 3诱导的细胞因子途径 对易感BALB/c小鼠T细胞的影响。此外，我们将确定CXCR 3水平是否可以 通过靶向这些途径在体内操纵，以努力改善BALB/c小鼠中的感染。最后我们 我们还将使用特异性的免疫细胞化学技术，研究B7：CD 28共刺激通路在CXCR 3调节T细胞中的作用。 途径激动剂和拮抗剂。这些补充办法应能使人们深入了解 CXCR 3在感染期间调节抗原特异性效应和记忆T细胞应答中的作用这些 这些研究很重要，因为它们不仅使我们能够优化治疗和疫苗策略， 通过靶向趋化因子及其受体来对抗微生物感染，但最终将有助于设计 治疗自身免疫性炎性疾病如类风湿性关节炎的免疫治疗方法 通过阻止致病性T细胞进入炎症部位。

Chemokines regulate the traffick and function of various immune effector cells and play a critical role in host defense against a variety of intracellular pathogens. The CXC chemokine receptor 3 (CXCR3) is expressed on plasmacytoid dendritic cells, neutrophils, natural killer (NK) cells, and T cells. CXCR3 ligands (CXCR3Ls), particularly CXCL9 (Mig) and CXCL10 (IP-10) are produced in high levels during Leishmania infection but their role in mediating protective immunity against leishmaniasis is poorly defined. We have shown previously that CXCR3 plays a key role in mediating immunity against cutaneous L. major infection in resistant C57BL/6 mice by controlling recruitment of CD4+ and CD8+ T cells to the infected skin and IFN-? production within the lesion. We have also found that CXCR3 is expressed on a significant proportion of memory T cells and is required for their migration to the dermis after re-challenge. Our preliminary studies show that T cells from L. majorsusceptible BALB/c mice, but not resistant C57BL/6 mice, fail to up-regulate CXCR3 upon activation despite producing comparable levels of IFN-? as C57BL/6 T cells. Our recent study shows that distinct cytokinedependent mechanisms control the expression of CXCR3 on CD4+ and CD8+ T cells. We have also found that the B7 co-stimulatory pathway is involved in maintaining and regulating CXCR3 expression on T cells in L. major-resistant mice. These findings lead us to hypothesize that CXCR3 regulates host resistance against L. major by controlling parasite-specific effector and memory T cell responses and that BALB/c mice have a defect in up-regulating CXCR3 on T cells which contributes to their susceptibility to L. major. The goals of this proposal are to asses the role of CXCR3 in regulation of Leishmania-specific effector and memory T cell responses during L. major infection and to determine how CXCR3 expression is controlled on T cells. (Aim 1) will examine the role of CXCR3 in regulation of antigen-specific effector CD4+ and CD8+ T cell responses during primary L. major infection in resistant C57BL/6 mice. (Aim2) will determine the role of CXCR3 in the regulation of memory T cell recruitment and function during L. major infection in C57BL/6 mice. (Aim 3) will determine the mechanisms by which the expression of CXCR3 is up-regulated on CD4+ and CD8+ T cells in C57BL/6 mice and will elucidate the cytokine pathways that are involved in preventing the induction of CXCR3 on T cells in susceptible BALB/c mice. In addition, we will determine whether CXCR3 levels can be manipulated in vivo by targeting these pathways in efforts to ameliorate infection in BALB/c mice. Finally, we will also study the role of B7:CD28 co-stimulatory pathway in CXCR3 regulation on T cells using specific pathway agonists and antagonists. These complementary approaches should provide insights into the role of CXCR3 in the regulation of antigen-specific effector and memory T cell responses during infection. These studies are important because they will not only enable us to optimize therapeutic and vaccine strategies against microbial infections by targeting chemokines and their receptors, but will eventually aid in designing immunotherapeutic approaches to treat autoimmune inflammatory diseases such as rheumatoid arthritis through blocking the recruitment of pathogenic T cells into the site of inflammation.