An immunologic mode of multigenerational transmission governs a gut Treg setpoint

At the species level, immunity depends on the selection and transmission of protectivecomponents of the immune system. A microbe-induced population of RORgamma-expressing T regulatory cells (Tregs) is essential in controlling gut inflammation. We uncovered a non-genetic, non-epigenetic, non-microbial, mode of transmission of their homeostatic setpoint. ROR gamma+ 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. ROR gamma+ Treg proportions negatively correlated with IgA production and coating of gut commensals, traits also subject to maternal transmission, in an immunoglobulin- and ROR gamma+ Treg-dependent manner. We propose a model based on a double-negative feedback loop, vertically transmittedvia 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.