An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint

Abstract

Highlights d Variations in gut RORg+ Tregs are maternally transmitted through multiple generations d RORg+ Treg setpoint is determined in early life, not driven by genetics or microbiota d Gut RORg+ Tregs and IgA form a double-negative regulatory loop d IgA+ plasma cells expand and migrate in late gestation via the entero-mammary axis

Synchronization of mothers and offspring promotes tolerance and limits allergy

“…An additional limitation of our work is that we focused on the effect of desynchronization on the development of colonic pTregs, and the effects of desynchronization may extend well beyond this cellular population and effects of alterations in EGF exposure. Indeed, recent studies have found that breast milk IgA levels inversely correlate with colonic RORγt + Tregs in the offspring and that this is a phenotype transmissible across generations (68). Future work will attempt to correlate allergic outcomes with desynchronization in humans and examine the effects of desynchronization beyond EGF and this cellular population.…”

Regulatory T Cells Developing Peri-Weaning Are Continually Required to Restrain Th2 Systemic Responses Later in Life

“…This process is regulated by maternal ligands present in breastmilk and bacterial components of the maturing microbiota around weaning, most notably epidermal growth factor ( 17 , 32 ). Maternal antibodies IgA and IgG also present in breastmilk have been shown to promote tolerance, may protect from food allergy pathogenesis in early life, and may help regulate development of RORγt+ pTregs ( 22 , 36 , 37 ). Following weaning, dietary antigens are largely encountered by the immune system in the small intestine, and dietary antigen-specific pTregs developing post-weaning have a limited life span in absence of antigen exposure ( 38 , 39 ).…”

“…A population of Tregs expressing the transcription factor RORγt+ differentiate early in life in a process driven by the microbiota, and may have unique capacities to avoid immunopathologies and restrain Th2 responses ( 21 , 22 ). Intriguingly this population of Tregs are reduced in children with food allergies ( 23 ).…”

Therapeutic Potential of the Intestinal Microbiota for Immunomodulation of Food Allergies

“…It is perhaps because generalized suppression of adaptive immunity at mucosal sites through excessive pTreg generation could be dangerous, as contact with facultative pathogens are frequent and risk of infections are high. Setting the correct bar for RORγt+ Tregs and homeostasis with the developing microbiota needs to occur in childhood, and seems to also be imprinted from the mother to the next generation by a double-negative loop involving maternally transmitted IgA ( 67 , 68 ). While this mechanism ensures that the next generation benefits from a maternal experience on the correct bar for a beneficial host-microbiota equilibrium, microbial adaptations are still able to fine-tune the level of RORγt+ Tregs throughout life and offer therapeutic options.…”