P06 (2026 - 2030) Lung-resident B cells as producers of Immunoglobulin A

Andreas Hutloff (CAU)

Project Summary 

Immunoglobulin A (IgA) is the key immunoglobulin for protecting mucosal surfaces against invading pathogens and may also protect against IgE-mediated allergic reactions. The key cytokine for IgA class-switch is TGF‑ß; however, additional cytokines and factors such as TLR stimuli, other bacterial products, or retinoic acid are involved in this process. IgA has the unique feature to be secreted into the mucosal lumen and can thus ideally provide even sterile immunity. Tissue-resident IgA memory cells can provide this protection directly in the mucosal tissue. The lung as one of the body's largest mucosal barrier organs is in constant exposure with the environment and is the entry site of many respiratory pathogens such as Mycobacterium tuberculosis, Influenza A, or SARS-CoV-2 virus. However, compared to the intestine, little is known about the mechanisms by which class switching to IgA is induced in the lung. Although most of the IgA directed against the natural microbiome is generated in a T cell-independent manner, high-affinity IgA against pathogens typically requires T cell help. T cell / B cell cooperation normally takes place in secondary lymphoid organs (SLO) such as Peyer's patches or lung-draining lymph nodes, where a highly structured microenvironment fosters the interaction of antigen-specific B cells with follicular T helper (Tfh) cells. As a very striking observation, our preliminary data indicate that IgA memory cells are exclusively found in the lung tissue but not the lung-draining lymph node. This difference is already established in the effector phase. With this project we want to understand why and how IgA+ B cells are only generated in the lung tissue but not the lung-draining lymph node. Therefore, factors from Tph cells and from lung-specific antigen-presenting cells such as interstitial macrophages which could be key for the selective IgA class switch in the lung will be analyzed in murine models in vivo. Understanding the mechanisms why and how lung resident IgA+ B cells are generated in the mucosal tissue but not the draining lymph nodes will open the gate to develop targeted strategies for the generation of tissue-resident IgA+ memory B cells for vaccination against respiratory pathogens.