Conference 2021 Live Talk
Maternal factors orchestrate multigenerational transfer of immune traits
Authors and Affiliations
Deepshika Ramanan1, Esen Sefik1, Silvia Galván-Peña1, Meng Wu1, Liang Yang1, Zhen Yang2, Aleksandar Kostic2, Tatyana V. Golovkina3, Dennis L. Kasper1, Diane Mathis1, Christophe Benoist1
1. Department of Immunology, Harvard Medical School, Boston MA 02115, USA
2. Joslin Diabetes Center and Department of Microbiology, Harvard Medical School, Boston MA 02115, USA
3. Department of Microbiology, Committee on Microbiology and Committee on Immunology, University of Chicago, Chicago, IL 60637, USA
Transmission of maternal factors in early childhood is crucial for the development and maintenance of long-term immune health, but the exact mechanisms by which they influence disease susceptibility in adulthood is unclear. Regulatory T cells (Tregs) are immune cells that are central to maintaining tolerance to microbes and food antigens in the intestine. Our lab and others have previously identified distinct subsets of intestinal Tregs, based on their expression of the transcription factors Helios, and Rorγ. The thymic Helios+ Tregs emigrate to the colon early in development and are unaffected by the intestinal microbiota. The Rorγ+ Tregs differentiate locally in response to intestinal microbes and appear around weaning age. The exact functions of these intestinal Treg subsets and the factors that determine their proportions are unclear. In our studies, we have found that maternal factors in early life determine proportions of intestinal Tregs, which can influence susceptibility to intestinal disease in adulthood.
We bred and cross-fostered commonly used inbred strains of mice, including C57Bl/6 and Balb/c. We analyzed proportions of intestinal Tregs and IgA+ plasma cells using flow cytometry. IgA levels were determined by analysis of stool and serum by flow cytometry and ELISA.
We found that the proportions of colonic Rorγ+ Tregs varied between different inbred strains of mice. Strikingly, these differences were maternally transferred during an early neonatal window, maintained throughout adulthood, and then transmitted through multiple generations in a non-genetic manner. During lactation, mothers transferred strain dependent differences in IgA to their offspring. The resulting differences in total IgA and IgA coating of microbes in neonates led to differential activation of intestinal T cells, which determined Rorγ+ Treg proportions in adults. Rorγ+ Tregs in turn regulated levels of intestinal IgA+ plasma cells, which migrated into the mammary gland during lactation, thus moderating IgA levels secreted in milk.
Our results demonstrate a novel mechanism of transmission of trans-generational immunity in early life via the “entero-mammary axis” that could potentially predispose adults to various inflammatory conditions.