Impact of Early Microbial Exposure on Immune Ontogeny

Principal Investigator: Brian Rudd

Department of Microbiology and Immunology
Sponsor: NIH-Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Grant Number: 5R01HD107798-03
Title: Impact of Early Microbial Exposure on Immune Ontogeny
Project Amount: $314,704
Project Period: September 2023 to August 2024

DESCRIPTION (provided by applicant): 

Evidence has shown that microbial exposure during critical stages of development can have long-lasting effects on the health status of an individual. However, there is currently no conceptual framework to explain how maternal microbial exposure shapes the fetal and adult immune systems. To fill this knowledge gap, we have developed a novel pet-shop mouse model and compared the ontogeny of CD8+ T cells in mice that were born from either ‘clean’ (SPF) or ‘dirty’ (pet-shop) mothers. Interestingly, the mice raised in the dirty environment mounted a more robust CD8+ T cell response and were highly resistant to infection. To understand how the ontogeny of the CD8+ T cell compartment was altered in the dirty mice, we used fate-mapping ‘timestamp’ mice and found a higher proportion of fast-acting fetal derived CD8+ T cells and fewer slow-acting adult derived CD8+ T cells present in the dirty mice. We also found that immune susceptibility could be normalized between clean and dirty mice by depleting the fetal layer of CD8+ T cells. These data indicate that maternal microbial exposure leads to an accumulation of fetal-derived CD8+ T cells that protects the host against intracellular pathogens. However, the underlying mechanisms remain undefined. Our hypothesis is that maternal microbial exposure alters developmental layering in the offspring by changing the dynamics of cell survival and peripheral selection of T cell receptors. In the first aim, we will combine our fate mapping approach with mathematical modeling to understand how maternal microbial exposure leads to an accumulation of fetal-derived CD8+ T cells. In the second aim, we will use paired single cell TCR/RNAseq to understand how the maternal microbial environments alters the TCR repertoire and immune defense. Knowledge gained from these studies is expected to provide a new conceptual model for understanding how maternal microbial colonization in early life can permanently program the offspring’s immune system and life-long disease risk.