Chemokines and regulation of T cell responses during infection

趋化因子调节多种免疫效应细胞的运输和功能，并在宿主中发挥关键作用 对多种细胞内病原体的防御。CXC趋化因子受体3(CXCR3)表达于 浆细胞样树突状细胞、中性粒细胞、自然杀伤(NK)细胞和T细胞。CXCR3配体(CXCR3L)， 尤其是CXCL9(Mig)和CXCL10(IP-10)在利什曼原虫感染期间大量产生，但它们的 在调节对利什曼病的保护性免疫中的作用尚不清楚。我们之前已经表明， CXCR3在C57BL/6耐药小鼠皮肤主要乳杆菌感染免疫中的关键作用 通过控制CD4+和CD8+T细胞向感染皮肤和干扰素？病变内的产物。 我们还发现，CXCR3在相当大比例的记忆T细胞上表达，并且是 他们迁移到真皮后重新挑战。我们的初步研究表明，来自主要致病乳杆菌的T细胞对 BALB/c小鼠，但不耐药的C57BL/6小鼠，在激活时未能上调CXCR3，尽管 产生类似水平的干扰素-？作为C57BL/6 T细胞。我们最近的研究表明，明显的细胞因子依赖 CXCR3在CD4+和CD8+T细胞上的表达调控机制。我们还发现， B7共刺激通路参与维持和调节T细胞CXCR3的表达。 具有重大抗性的小鼠。这些发现使我们推测CXCR3调节寄主对L. 主要通过控制寄生虫特异性效应和记忆T细胞反应，BALB/c小鼠具有 T细胞上CXCR3上调的缺陷，导致其对主要乳杆菌的易感性。这样做的目的是 建议评估CXCR3在调节利什曼原虫特异性效应器和记忆T细胞中的作用 并确定CXCR3在T细胞上的表达是如何调控的。(目标1) 将研究CXCR3在调节抗原特异性效应分子CD4+和CD8+T细胞反应中的作用 在耐药C57BL/6小鼠原发感染期间。(AIM2)将决定CXCR3在 大型钩端螺旋体感染对C57BL/6小鼠记忆T细胞募集和功能的调节(目标3)意志 CXCR3上调CD_4~+和CD_8~+T细胞表达的机制 并将阐明参与阻止CXCR3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CXCR3水平是否可以 通过靶向这些途径在体内进行操作，以努力改善BALB/c小鼠的感染。最后，我们 还将研究B7：CD28共刺激通路在CXCR3对T细胞的调节中的作用 途径激动剂和拮抗剂。这些相辅相成的方法应该让我们深入了解 CXCR3在感染过程中对抗原特异性效应和记忆T细胞反应的调节这些 研究是重要的，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 类风湿性关节炎等自身免疫性炎症性疾病的免疫治疗方法 通过阻断致病T细胞的募集进入炎症部位。

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.