Regulation of Type 1 Diabetes Development and B-cell Activation in Nonobese Diabetic Mice by Early Life Exposure to a Diabetogenic Environment

PLoS One. 2017 Aug 3;12(8):e0181964. doi: 10.1371/journal.pone.0181964. eCollection 2017.

Abstract

Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90% by 30 weeks in females). NODhigh mice harbored more complex intestinal microbiota, including several pathobionts; both colonies harbored segmented filamentous bacteria (SFB), thought to suppress T1D. Young NODhigh females had increased B-cell activation in their mesenteric lymph nodes. These phenotypes were transmissible. Co-housing of NODlow with NODhigh mice after weaning did not change T1D development, but T1D incidence was increased in female offspring of co-housed NODlow mice, which were exposed to the NODhigh environment both before and after weaning. These offspring also acquired microbiota and B-cell activation approaching those of NODhigh mice. In NODlow females, the low rate of T1D was unaffected by cyclophosphamide but increased by PD-L1 blockade. Thus, environmental exposures that are innocuous later in life may promote T1D progression if acquired early during immune development, possibly by altering B-cell activation and/or PD-L1 function. Moreover, T1D suppression in NOD mice by SFB may depend on the presence of other microbial influences. The complexity of microbial immune regulation revealed in this murine model may also be relevant to the environmental regulation of human T1D.

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • B7-H1 Antigen / metabolism
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / epidemiology
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Environment*
  • Female
  • Incidence
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred NOD
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • B7-H1 Antigen
  • Cytokines