An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint

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. [Display omitted] •Variations in gut RORγ+ Tregs are maternally transmitted through multiple generations•RORγ+ Treg setpoint is determined in early life, not driven by genetics or microbiota•Gut RORγ+ Tregs and IgA form a double-negative regulatory loop•IgA+ plasma cells expand and migrate in late gestation via the entero-mammary axis The homeostatic level of regulatory T cells in the colon is transmitted across generations and is modulated by maternally transferred IgA.