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

• Applicant: Professor Dr. Andreas Hutloff
• Subject Area: Immunology ; Pneumology, Thoracic Surgery
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396826694

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.

• DFG Programme: Research Grants