Microbial exposure in early life alters the ontogeny and function of CD8+ T cells

Abstract

Abstract Evidence has shown that microbial exposure in early life can have long-lasting effects on the health status of an individual. However, the underlying basis of how microbes shape the immune system is not well understood. In this study, we utilized a novel pet shop mouse model and compared the immune development and function of laboratory mice raised in either a clean (SPF) or dirty (pet-shop) environment. When we challenged the two groups with an intracellular pathogen in adulthood, we found that mice raised in the dirty environment mounted a more robust CD8+ T cell response and were highly resistant to infection. Adoptive transfer experiments with CD8+ T cells from clean and dirty mice into T cell deficient recipients indicated that differences in immune susceptibility were linked to changes in the CD8+ T cell compartment. Moreover, the dirty mice had an increased accumulation of antigen-specific CD8+ T cells and produced more effector molecules. To understand how the ontogeny of the CD8+ T cell compartment was altered in the dirty mice, we used our 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 found that immune susceptibility could be normalized between clean and dirty mice by depleting the fetal layer of CD8+ T cells. Collectively, these findings suggest that microbial exposure leads to permanent changes in the immune system by altering the developmental layering of the peripheral T cell compartment. We are currently using a combination of RNA- and ATAC-seq to gain a deeper understanding of how the microbial environment mediates changes to CD8+ T cells at the gene regulatory level.