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

不变性自然杀伤T细胞（iNKT）被称为先天样T细胞亚群，具有快速和强大的细胞因子反应能力，使其在各种免疫过程中发挥重要作用。尽管iNKT细胞具有与传统T细胞相同的特征，但iNKT细胞具有有限的T细胞受体库，可识别CD1d呈递的糖脂/磷脂抗原。该领域的最新研究提出将iNKT细胞根据其功能特性细分为三个亚群（iNKT1， iNKT2和iNKT17）。然而，iNKT亚群之间的发育联系仍然很模糊，这需要对iNKT亚群的分化途径进行更详细的研究。近年来，另一类先天免疫细胞被称为先天淋巴样细胞（ILCs），引起了人们的广泛关注。尽管其表面缺乏T细胞受体（TCR），但ilc在功能水平上与iNKT细胞亚群具有惊人的相似性，最近在转录水平上也被证明是正确的。作为iNKT细胞，ilc被细分为3个效应组，在各种免疫反应中发挥关键作用，包括驱逐蠕虫感染。后一种机制涉及肠上皮簇状细胞的化学感觉激活，促进其增殖和IL-25的产生。这反过来又导致ILCs扩增和IL-13/IL-4生成反应，从而清除蠕虫。因此，根据iNKT和ILCs细胞亚群之间的密切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群可以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，本研究旨在阐明IL-25调控中可能存在的化学感觉信号通路以及共生菌群对其的影响。同时，本研究将重点研究几种细胞因子在iNKT1和iNKT17细胞亚群发育和效应功能中的作用。这部分研究将包括稳态条件下的实验和胸腺损伤模型。拟议的研究项目收集的数据和见解将进一步揭示iNKT细胞发育步骤及其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.