IL-21 dependent immunity to microsporidia

描述(由申请人提供)： 由于CD8+T细胞能够产生细胞因子并表现出对感染靶标的杀伤活性，因此在抵御多种细胞内病原体方面发挥着关键作用。自去年以来 几年来，有报道称，对这些感染性病原体复制的卓越控制依赖于这些细胞发挥多种功能的能力。其中许多研究是在艾滋病毒感染者身上进行的，已经证明，非进展者(那些没有出现症状感染的人)保持着高水平的多功能反应，但在感染进展的受试者中并非如此。此外，针对病毒感染的疫苗方案的成功也与其诱导强大的多功能CD8+T细胞反应的能力有关。我们实验室的最新数据表明，多功能细胞的重要性不仅限于病毒感染，还可以扩展到真菌病原体，如微孢子虫，这是导致HIV感染人群发病率/死亡率的重要机会性病原体。该提议的初步数据表明，宿主保护强烈依赖于其发展强大的多功能CD8+T细胞反应的能力。然而，导致多功能短命效应细胞(SLEC)和记忆前体效应细胞(MPEC)反应发生的因素(S)还没有得到很好的研究，也没有确定诱导它们的细胞因子。我们实验室的初步研究表明，CD4+T细胞中的FTH(滤泡T辅助细胞)亚群是IL-21的主要产生者，在诱导Thi对微孢子虫感染的反应中起着关键作用。在这项计划中，我们计划研究FTH免疫对微孢子虫感染的诱导及其在多功能SLEC/MPEC反应发展中的重要性和机制。此外，在免疫受损的情况下，如艾滋病毒感染，当CD_4+T细胞反应被严重下调时，可以探索诱导和维持这些细胞多功能的替代机制(S)将被测试。该提案包括三个具体目标。在第一个特定目标中，将确定FTH对微孢子虫感染的反应的诱导动力学和诱导机制。此外，还将分析它们在多功能SLEC和MPEC反应中的作用。第二个具体目标将涉及FTH/IL-21在多功能SLEC和MPEC群体向记忆反应转变中的作用。此外，FTH/IL-21在维持长期记忆反应中的重要性将被检测。最后，在第三个特定目标中，将确定gd T细胞在缺乏最佳CD4+T细胞免疫的情况下，如在HIV感染期间，在功能性SLEC和MPEC反应中的作用。

DESCRIPTION (provided by applicant): Due to their ability to produce cytokines and exhibit cytolytic activity against infected targets, CD8+ T cells are critical role for protection against number of intracellular pathogens. Since last few years it has been reported that superior control of replication of these infectious agents is dependent on the ability of these cells to display multiple functions. Many of these studies have been carried out with HIV infected individuals and it has been demonstrated that non-progressors (those who do not develop symptomatic infection) maintain high levels of multifunctional response, which is not the case in the subjects where infection progresses. Moreover, the success of vaccine regimens against viral infection has also been linked to its ability to induce robust multifunctional CD8+ T cell response. Recent data from our laboratory suggests that importance of multifunctional cells cannot be restricted to viral infections and can be extended to fungal pathogens like microsporidia an important opportunistic pathogen that causes morbidity/ mortality in HIV infected population. Preliminary data for the proposal demonstrates that host protection is strongly dependent on its ability to develop a strong polyfunctional CD8+ T cell response. However, factor (s) responsible for the development of robust polyfunctional SLEC (short-lived effector cell) and MPEC (memory precursor effector cell) response has not been well studied and cytokine responsible for their induction has not been identified. Preliminary studies from our laboratory suggest that FTH (Follicular T helper cells) subset of CD4+ T cells, main producers of IL- 21 play a pivotal role in the induction of thi response to microsporidial infection. In this proposal we plan to study the induction of FTH immunity against the microsporidial infection and their importance and mechanism in the development of multifunctional SLEC/ MPEC response. Moreover, in an immune-compromised situation like HIV infection, when CD4+ T cell responses are severely down-regulated alternate mechanism(s) that can be explored to induce and maintain the multifunctional ability of these cells will be tested. The proposal comprises of three specific aims. In the first specific aim kinetics, induction and mechanism of induction of FTH response against microsporidial infection will be determined. Further their role in the development of multifunctional SLEC and MPEC response will be assayed. The second specific aim will involve the role of FTH/IL-21 in the transition of multifunctional SLEC and MPEC population to memory response. Further, importance of FTH/IL-21 in maintenance of long-term memory response will be assayed. Finally in the third specific aim role of gd T cells in the development of functional SLEC and MPEC response in the absence of optimal CD4+ T cell immunity, like during HIV infection will be determined.