Memory T and B cells in the lung and their role for local and systemic immunity

免疫记忆是适应性免疫系统的一个重要特征。高亲和力抗体和特化效应T细胞有效地保护我们的身体免受入侵病原体的侵害。这也是所有疫苗接种策略的基本原则。然而，与此同时，错误定向的记忆T细胞和B细胞在针对自身（如自身免疫性疾病）或针对无害的环境抗原（如过敏症）时会构成重大威胁。因此，更好地了解记忆T细胞和B细胞是如何产生和维持的具有重要的临床意义。T细胞/B细胞合作通常发生在次级淋巴器官中，其中特化的T滤泡辅助（Tfh）细胞亚群为B细胞分化为记忆和长寿浆细胞提供帮助。我们的小组最近发现了外周T辅助细胞（Tph）的新群体，在炎症的非淋巴组织中执行相同的功能。我们的研究重点是肺的免疫反应，肺是主要的免疫屏障器官之一，不仅对呼吸道病原体的保护很重要，而且还涉及几种慢性炎症性疾病。我们最近发现Tph和B细胞在结节病中起核心作用，这是我们对该病发病机制理解的一个范式转变。使用小鼠肺部炎症模型，结节病患者的各种组织样本和多组学技术，如光谱流式细胞术，单细胞RNA测序和多参数免疫组织学，我们计划进一步剖析不同的循环和组织驻留Tph，Tfh和记忆B细胞群的表型和功能。特别是，我们将解决Tfh和Tph细胞和记忆B细胞亚群与不同抗原亲和力的功能之间的关系仍然是个谜。在该项目的更多翻译部分，我们将在更大的结节病患者队列中测试循环Tph细胞如何用作疾病活动的生物标志物。最后，我们将利用我们对结节病中B细胞的新认识，提出一种新的策略，以确定仍然未知的致病因子。将在免疫组织学中使用克隆扩增的结节病B细胞的特异性表达抗体，以确定识别抗原的性质。总之，这些实验将大大增加我们对各种循环和组织驻留的T和B记忆子集的了解。这将为消除慢性炎症器官中的致病性T和B细胞或促进组织驻留记忆T和B细胞的发育提供基础，作为屏障器官如肺中的第一道防线。

Immunological memory is a key feature of the adaptive immune system. High-affinity antibodies and specialized effector T cells efficiently protect our body from invading pathogens. This is also the basic principle of all vaccination strategies. At the same time, however, misdirected memory T and B cells can pose a major threat when they are directed either against self, as in autoimmune diseases, or against innocuous environmental antigens, as in allergies. A better understanding of how memory T and B cells are generated and maintained is therefore of paramount clinical importance. T cell/B cell cooperation normally occurs in secondary lymphoid organs, where the specialized subpopulation of T follicular helper (Tfh) cells provide help for B cell differentiation into memory and long-lived plasma cells. Our group has recently discovered the novel population of peripheral T helper cells (Tph) that perform the same functions in inflamed non-lymphoid tissues. Our research focuses on immune responses in the lung, one of the major immunological barrier organs, which is not only important for protection against respiratory pathogens but also involved in several chronic inflammatory diseases. We have recently shown that Tph and B cells play a central role in sarcoidosis, a paradigm shift in our understanding of the pathogenesis of this disease. Using a mouse model of lung inflammation, various tissue samples from sarcoidosis patients and multi-omics techniques such as spectral flow cytometry, single cell RNA sequencing and multi-parametric immunohistology, we plan to further dissect the phenotype and function of different circulating and tissue-resident Tph, Tfh and memory B cell populations. In particular, we will address the still enigmatic relationship between Tfh and Tph cells and the function of memory B cell subsets with different antigen affinities. In a more translational part of the project, we will test in a larger cohort of sarcoidosis patients how circulating Tph cells can be used as a biomarker for disease activity. Finally, we will use our new knowledge about B cells in sarcoidosis for a new strategy to identify the still unknown disease-causing agent. Recombinantly expressed antibodies from clonally expanded sarcoidosis B cells will be used in immunohistology to define the nature of the recognized antigen. Together, these experiments will substantially increase our knowledge of the various circulating and tissue-resident T and B memory subsets. This will provide the basis for either eliminating pathogenic T and B cells from chronically inflamed organs or promoting the development of tissue-resident memory T and B cells as a first line of defense in barrier organs such as the lung.