Remodeling of lymph node-derived cytokine responses at the infected tissue site

描述（由申请人提供）：免疫反应的区隔化确保了淋巴（LN）中T细胞活化的严格调节和炎症部位的精确效应T细胞递送和功能。在LN中，初始辅助性（Th） CD4+ T细胞获得特化功能并获得明显的归巢潜能。因此，在LN的分化过程中，效应细胞的功能和随后的定位似乎都是预先确定的。我们最近对原生动物利什曼原虫的研究表明，这种组织特异性的细胞因子分泌效应细胞的积累可以被感染组织部位的病原体破坏。L. major在感染组织部位施加选择性T细胞细胞因子反应，独立于病原体对LN启动库的影响。早期的细胞因子库（IL-4和IFN3产生者的混合物）在感染组织中被修饰，在操作上包括IL-4而不包括IFN3产生者。我们假设，L. major通过破坏利什曼菌、ifn3产生菌的免疫效应物的积累或活性来操纵组织部位的免疫反应。我们已经做了三个关键的观察，给我们一个新的处理在感染部位的反应调节。首先，L. major抑制感染真皮中1型趋化因子的表达，部分是通过直接作用于感染的巨噬细胞。其次，L. major诱导CCL1和CCL7两种2型趋化因子的表达。最后，感染耳中局部IL-4的产生负向调节IFN3的产生。使用一套独特的工具来原位跟踪对L. major的新兴免疫反应，本提案旨在确定这种早期病原体-宿主相遇的关键成分，这些成分调节受感染组织中的Th细胞因子库。特异性目标1将测试一系列解释细胞因子库变化的假设：免疫效应物的差异募集/保留或进入组织但随后的功能改变。特异性目标2将验证这一假设，即L. major调节趋化因子环境，导致IL-4产生者的招募，而不是利什曼原虫ifn3产生者的招募。反过来，IL-4的产生通过复合选择性趋化因子环境和/或直接抑制Th1效应物的功能而放大了这种限制。在感染组织部位进行细胞因子编辑的概念对免疫治疗具有重要意义。开发利用多种LN库的方法，通过操纵招募到感染部位的效应物的类型来重新调整感染部位的免疫反应，对许多疾病状态具有巨大的治疗潜力。主要在感染组织部位施加选择性T细胞细胞因子反应，独立于病原体对淋巴细胞库启动的影响。因此，了解组织部位的病原体特异性调节机制成为设计适当治疗方法的关键。开发利用不同淋巴结库的方法，通过操纵招募到感染部位的效应物的类型来重新调整感染部位的免疫反应，对许多疾病状态具有巨大的治疗潜力。

DESCRIPTION (provided by applicant): Compartmentalization of the immune response ensures tight regulation of T cell activation in the lymph node (LN) and precise effector T cell delivery and function at sites of inflammation. In the LN, naive helper (Th) CD4+ T cells acquire specialized functions and acquire distinct homing potential. Therefore both function and subsequent localization of effector cells appears to be pre-determined during differentiation in the LN. Our recent studies with the protozoa Leishmania major suggest that such tissue-specific accumulation of cytokine secreting effector cells can be subverted by a pathogen at the infected tissue site. L. major imposes a selective T cell cytokine response at the infected tissue site, independent of pathogen effects on LN priming of the repertoire. The early cytokine repertoire exiting the LN (a mixture of IL-4 and IFN3 producers) is modified at the infected tissue to operationally include IL-4 but not IFN3 producers. We hypothesize that L. major manipulates the immune response at the tissue site by subverting the accumulation or activity of leishmaniacidal, IFN3-producing, immune effectors. We have made three key observations that give us a novel handle on the regulation of responses at the infection site. Firstly, L. major inhibits the expression of Type 1 chemokines in the infected dermis, in part through direct action on the infected macrophage. Secondly, L. major induces the expression of two Type 2 chemokines, CCL1 and CCL7. Finally, local IL-4 production negatively regulates IFN3 production in the infected ear. Using a unique set of tools to track, in situ, an emerging immune response to L. major, this proposal seeks to identify key components of this early pathogen-host encounter that modulate the Th cytokine repertoire in the infected tissue. Specific Aim 1 will test a series of hypotheses accounting for changes in cytokine repertoire: differential recruitment/retention of immune effectors or entry into the tissue but subsequent functional modification. Specific Aim 2 will test the hypothesis is that L. major modulates the chemokine milieu resulting in the recruitment of IL-4 producers but not leishmaniacidal IFN3-producers. In turn, IL-4 production amplifies the restriction by compounding the selective chemokine milieu and/or directly inhibiting Th1 effector function. The concept of cytokine editing at the infected tissue site has important implications for immune therapy. Developing ways of harnessing a diverse LN repertoire to retune immune responses at the infection site, by manipulating the type of effectors recruited to the site, has great therapeutic potential for many disease states. PUBLIC HEALTH REVELANCE L. major imposes a selective T cell cytokine response at the infected tissue site, independent of pathogen effects on LN priming of the repertoire. Understanding pathogen-specific mechanisms of regulation at the tissue site therefore becomes key to the design of appropriate therapeutics. Developing ways of harnessing a diverse lymph node repertoire to retune immune responses at the infection site, by manipulating the type of effectors recruited to the site, has great therapeutic potential for many disease states.