An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint

Cell. 2020 Jun 11;181(6):1276-1290.e13. doi: 10.1016/j.cell.2020.04.030. Epub 2020 May 12.


At the species level, immunity depends on the selection and transmission of protective components of the immune system. A microbe-induced population of RORγ-expressing regulatory T cells (Tregs) is essential in controlling gut inflammation. We uncovered a non-genetic, non-epigenetic, non-microbial mode of transmission of their homeostatic setpoint. RORγ+ Treg proportions varied between inbred mouse strains, a trait transmitted by the mother during a tight age window after birth but stable for life, resistant to many microbial or cellular perturbations, then further transferred by females for multiple generations. RORγ+ Treg proportions negatively correlated with IgA production and coating of gut commensals, traits also subject to maternal transmission, in an immunoglobulin- and RORγ+ Treg-dependent manner. We propose a model based on a double-negative feedback loop, vertically transmitted via the entero-mammary axis. This immunologic mode of multi-generational transmission may provide adaptability and modulate the genetic tuning of gut immune responses and inflammatory disease susceptibility.

Keywords: IgA; Rorγ+; Tregs; colonic Tregs; entero-mammary axis; maternal transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Digestive System / immunology*
  • Disease Susceptibility / immunology
  • Female
  • Gastrointestinal Microbiome / immunology
  • Homeostasis / immunology
  • Immunoglobulin A / immunology
  • Inflammation / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Inbred NOD
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • Immunoglobulin A
  • Nuclear Receptor Subfamily 1, Group F, Member 3