Deciphering endogenous and environmental factors impacting on development and function of iNKT cell subsets

不变自然杀伤T细胞(INKT)是一类先天的T细胞亚群，具有快速、强健的细胞因子反应能力，在多种免疫过程中发挥重要作用。尽管iNKT细胞具有传统T细胞的共同特征，但它具有识别CD1d提呈的糖脂/磷脂抗原的有限的T细胞受体谱系。该领域的最新研究提出根据iNKT细胞的功能特性将其细分为三个亚集(iNKT1、iNKT2和iNKT17)。然而，iNKT亚群之间的发育相互关系仍然不清楚，这需要对iNKT亚群的分化途径进行更详细的研究。近年来，另一类被称为先天性淋巴组织细胞(Ingenate Lymphid Cells，ILCs)的先天性免疫细胞受到了极大的关注。尽管ILCs表面缺乏T细胞受体(TCR)，但在功能水平上与iNKT细胞亚群有惊人的相似之处，最近在转录水平上也是如此。作为iNKT细胞，ILC被细分为树效应群，在包括驱逐蠕虫感染在内的各种免疫反应中起着至关重要的作用。后一种机制涉及到肠上皮绒毛细胞的化学感觉激活，推动其增殖和IL-25的产生。这反过来会导致ILC的扩张和IL-13/IL-4产生的反应，从而清除蠕虫。因此，根据iNKT和ILCS细胞亚群之间的相似性以及最近在胸腺中发现的簇状细胞，我们假设肠道微生物区系可能通过化学感觉信号通路影响胸腺iNKT细胞亚群的发育。因此，本研究旨在研究胸腺簇样细胞局部产生IL-25对iNKT2细胞发育和功能的可能影响。此外，还试图阐明参与IL-25调节的化学感觉信号通路以及共生微生物区系对其的相应影响。同时，这项研究将重点研究两种细胞因子的作用，这些细胞因子被认为是控制iNKT1和iNKT17细胞亚群的发育和效应功能的因素。这部分研究将包括在稳态条件下和胸腺损伤模型中的实验。拟议的研究项目收集的数据和见解将进一步揭开iNKT细胞发育步骤和它们形成的功能网络的难以捉摸的本质。

Invariant natural killer T (iNKT) cells are referred as an innate-like T cell subset with the capacity for fast and robust cytokine response granting them prominent roles in diverse immune processes. Although sharing common features with conventional T cells, iNKT cells possess a limited T cell receptor repertoire recognizing glycolipid/phospholipid antigens presented by CD1d. The latest studies in the field proposed a subdivision of the iNKT cells into three (iNKT1, iNKT2 and iNKT17) subsets in accordance to their functional properties. However, the developmental interconnections between the iNKT subsets still remain vague which requires more detailed studies of the differentiation pathways of the iNKT subsets.In the recent years another group of innate immune cells termed innate lymphoid cells (ILCs) gained huge attention. Despite the lack of T cell receptor (TCR) on their surface, ILCs were shown to share astonishing resemblance at functional level with iNKT cell subsets which recently was shown to be true at transcriptional level as well. As iNKT cells, ILCs are subdivided into tree effector groups shown to be crucial in various immune responses including expulsion of helminths infection. The latter mechanism involves chemosensory activation of intestinal epithelial tuft cells propelling their proliferation and IL-25 production. This in turn leads to ILCs expansion and an IL-13/IL-4 coined response resulting in clearance from the worms. Therefore, guided by the close resemblance between iNKT and ILCs cell subsets and a recent discovery of tuft-like cells in the thymus, we hypothesize that intestinal microbiota can impact on the development of thymic iNKT cell subsets via chemosensory signalling pathways. Hence, this proposal is aiming at investigating the possible impact of local IL-25 production by thymic tuft-like cells on iNKT2 cell development and function. In addition, it is intended to elucidate a putative chemosensory signalling pathway involved in the IL-25 regulation and the corresponding influence of symbiotic microbiota on it. In parallel, this study will focus on examining the role of a couple of cytokines presumed to govern the development and the effector functions of iNKT1 and iNKT17 cell subsets. This part of the study will include experiments in steady-state conditions and in a thymus injury model.The data and the insights gathered by the proposed research project would be a further step in unravelling the elusive nature of iNKT cells developmental steps and functional networks they form.