Homeostatic and infection-induced adaptive immunity in the neonatal small intestine and its functional consequences

• Applicant: Dr. Natalia Torow, Ph.D.
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321169432

The intestinal mucosa has to perform an intricate task maintaining tolerance towards the myriads of innocuous food and microbial antigens but remaining responsive towards enteric pathogens. In the adult intestine a competitive microbiota, a continuously renewing epithelium and an effective highly structured adaptive immune system facilitate this task. In the neonate gut, the situation, however, is dramatically different. With rupture of membranes, the neonatal mucosa is rapidly colonized by commensal bacteria. Major adaptive and developmental changes of the tissue architecture, immune cell composition and function accompany this process to establish host microbial homeostasis. In the event of microbial challenge, these mechanisms might, however, contribute to the enhanced susceptibility of the neonate to infection. Indeed, enteric infections in young infants represent a major cause of childhood mortality worldwide. I have previously performed a systematic characterization of the immune cell composition in the neonate, infant and adult small intestine. Whereas myeloid cell populations were already present at birth and remained stable from birth to adulthood, the kinetic of adaptive lymphoid cell populations was very dynamic. T lymphocytes colonized the Peyers patches soon after birth. Surprisingly, these cells remained naïve even in the presence of microbiota until after weaning. The naivety of T cells in the neonate intestine could partly be explained by the presence of maternal IgA and regulatory T cells. Age-dependent differences in the uptake, processing and presentation of luminal antigen by myeloid cells may critically contribute to this phenomenon in the neonate but have so far remained undefined. Further, the influence of premature T cell activation for long-term immune homeostasis and the susceptibility to immune mediated diseases has not been examined. In the proposed research project I will investigate the routes of luminal antigen uptake, transport and processing in the small intestine of neonatal mice. This includes the analysis of mechanisms that facilitate premature immune stimulation and the effect of immune stimulation in the neonate intestine on the life-long susceptibility to immune-mediated diseases. I expect that a better understanding will allow the development of new preventive and therapeutic strategies for infectious and inflammatory diseases in the neonate host and a better knowledge of the etiology of immune-mediated diseases during later life.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Mathias Walter Hornef