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

不变的自然杀伤T（iNKT）细胞被称为具有快速和稳健的细胞因子应答能力的先天性样T细胞亚群，赋予它们在多种免疫过程中的突出作用。虽然与常规T细胞共享共同特征，但iNKT细胞具有有限的T细胞受体库，其识别由CD 1d呈递的糖脂/磷脂抗原。该领域的最新研究提出了根据其功能特性将iNKT细胞细分为三个亚群（iNKT 1，iNKT 2和iNKT 17）。然而，iNKT各亚群之间的发育关系尚不清楚，需要对iNKT各亚群的分化途径进行更深入的研究。近年来，另一类称为先天淋巴样细胞（innate lymphoid cells，ILC）的先天免疫细胞引起了人们的极大关注。尽管ILC表面缺乏T细胞受体（TCR），但其在功能水平上与iNKT细胞亚群具有惊人的相似性，最近在转录水平上也显示出这种相似性。作为iNKT细胞，ILC被细分为三个效应物组，这些效应物组在包括驱逐蠕虫感染在内的各种免疫应答中至关重要。后一种机制涉及肠上皮簇细胞的化学感受性激活，推动其增殖和IL-25产生。这又导致ILC扩增和IL-13/IL-4联合应答，导致从蠕虫中清除。因此，根据iNKT和ILC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受信号通路影响胸腺iNKT细胞亚群的发育。因此，本提案旨在研究胸腺簇样细胞局部产生IL-25对iNKT 2细胞发育和功能的可能影响。此外，它的目的是阐明一个假定的化学感受信号通路参与IL-25的调节和相应的共生菌群的影响it. In平行的，本研究将集中在检查的作用，一对夫妇的细胞因子假定支配的发展和iNKT 1和iNKT 17细胞亚群的效应器功能。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性质。

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.