IgA-select – B cell selection and antibody function in intestinal antibody responses to microbiota

• Applicant: Professor Dr. Tim Rollenske
• Subject Area: Immunology ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506620580

At birth, the intestine is colonized by commensal microbes which will form a relatively stable personal microbial community impacting almost any aspect of our health. Microbial colonization elicits intestinal antibody responses that are dominated by Immunoglobulin A (IgA), the most abundant antibody isotype at mucosal surfaces in mammals. In general, protective antibody responses are well-studied in context of infection, however, how antibodies at mucosal surfaces aid to establish host-microbial mutualism and keep homeostasis between the host and its microbiota is poorly understood. By combining gnotobiotic techniques with single B cell receptor repertoire sequencing, monoclonal antibody generation and testing and a variety of other immunological methods, we address three major research questions in the field of IgA biology in IgA-select: i) if the intestinal antibody response is prone to select functional bacteria cross-reactive IgA, ii) how luminal secretory (S)IgA modulates the intestinal antibody response, and iii) if the selective pressure opposed by antigen-specific SIgA on the bacteria leads to immune evasion of the microbiota long-term. To be able to address these research questions at molecular and mechanistic detail, we use different reductionist approaches which are based on newly designed mouse model systems of limited bacteria-reactive antibody specificities and the capability to work under hygiene conditions of defined reduced microbiota diversity. Further, if appropriate, we select bacterial model strains which are not only common members of the human microbiota but also opportunistic pathogens. The generated monoclonal antibodies that are characterized in our studies have therefore the potential to be used as pre-emptive therapy or treatment option in human infections. Overall, understanding the effects of SIgA on the microbiota’s physiology and stability is important to understand biological in vivo mechanisms in health and may allow manipulation of the microbiota to promote health. Further, the modulation of the host immune response by SIgA may enable and improve mucosal vaccination strategies which is a desirable goal for all vaccines targeting pathogens that primarily infect mucosal sites.

• DFG Programme: Independent Junior Research Groups