EARLY-LIFE EXPOSURES TO SPECIFIC COMMENSAL MICROBES TRAIN THE IMMUNE SYSTEM AND PREVENT TYPE 1 DIABETES

Early-life disruptions of the gut microbiome have long-lasting impacts on the developing immune system, yet how the composition of the early-life microbiota contributes to autoimmunity is unclear. Here we find that a rationally-designed consortium of 9 culturable bacteria (PedsCom) that dominate the early-life microbiome of diabetes-protected NOD/Eα16 mice confers protection from developing type 1 diabetes (T1D) in diabetes-susceptible NOD mice. PedsCom colonization induces weaning-associated peripheral regulatory T cells (pTregs) in the intestines and pancreatic lymph nodes while restraining IFNγ in the pancreatic islets. Remarkably, this protection from developing T1D is completely dependent on early-life colonization of NOD mice by PedsCom, thereby demonstrating a critical time window in which specific commensal microbes induce tolerance. During this critical time window of early-life colonization and immune development, specific microbes unexpectedly translocate from the gut to peripheral tissues in a process we call “physiologic translocation”. Some translocating microbes induce tolerogenic responses such as pTregs while others induce systemic anti-commensal antibodies. IgA deficiency enhances anti-commensal antibodies levels, suggesting that mucosal IgA may impacts localization of commensal microbes to restrain systemic immune responses. The removal of the 3 strongest pTregs inducing commensals from the PedsCom consortium led to an increase in the rate of type 1 diabetes in NOD mice. Altogether these results demonstrate that exposure to specific commensal bacteria during this developmental window protects from autoimmunity and suggests that localization of these commensal bacteria may drive this protection. These findings highlight the potential risk of disrupting early host and commensal relationships and have implications for developing microbial therapies that target the early-life microbiome.

Author dc:creator

• Green, Jamal, L

Advisors dc:contributor.advisor

• Silverman, Michael, A
• Eisenlohr, Laurence, C

• Immunology and Infectious Disease
• Microbiology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/60048

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/60048