The role of early microbial exposure in the ontogeny of CD8+ T cells

Project Summary/Abstract The amount of microbial exposure an individual experiences in utero and early in life has a lasting and profound impact on their immune status later in life. A growing number of reports have associated exposure to a diverse range of microbes with an enhanced immune response against unrelated pathogens. However, the mechanisms

in which the microbial environment shapes the development of the immune system is unknown. To provide insight into this question, we modified the ‘pet-shop’ mouse model so that laboratory mice would be exposed to pathogens for the entirety of their development. Interestingly, we found mice raised in a ‘dirty’ environment have

enhanced immune protection against intracellular infections, which was associated with changes in the CD8+ T cell compartment. To understand how the CD8+ T cell compartment was altered in a ‘dirty’ environment, we used our ‘timestamp’ mice and tracked the fates of T cells produced at different stages of life. We found that

increased resistance to intracellular pathogens was linked to a higher proportion of ‘fast-acting’ fetal-derived CD8+ T cells and lower proportion of ‘slow-acting’ adult-derived CD8+ T cells present in adulthood. These data suggests that microbial exposure in early life leads to permanent changes in the immune system by altering the

developmental layering of the peripheral T cell compartment. The main goal of this proposal is to identify the key mechanisms that alter the developmental layering of CD8+ T cells in dirty mice. In aim 1, I will determine how the production and maintenance of CD8+ T cells is altered in dirty mice. In aim 2, I will assess how cell-intrinsic

and environmental factors contribute to the altered composition of CD8+ T cells in dirty mice. This proposal aims to create a conceptual framework to understand how microbial exposure in early life alters the development of the CD8+ T cell compartment. Knowledge gained from this proposal has the potential to result in a paradigm

shift of how we understand immune ontogeny and immune cell instruction.