Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice

J Clin Invest. 2009 Jun;119(6):1515-23. doi: 10.1172/JCI38503. Epub 2009 May 26.

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of insulin-producing beta cells. Viral infections induce immune responses that can damage beta cells and promote T1D or on the other hand prevent the development of the disease. However, the opposing roles of viral infections in T1D are not understood mechanistically. We report here that viruses that do not inflict damage on beta cells provided protection from T1D by triggering immunoregulatory mechanisms. Infection of prediabetic NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus (LCMV) delayed diabetes onset and reduced disease incidence. Delayed T1D onset was due to transient upregulation of programmed cell death-1 ligand 1 (PD-L1) on lymphoid cells, which prevented the expansion of diabetogenic CD8+ T cells expressing programmed cell death-1 (PD-1). Reduced T1D incidence was caused by increased numbers of invigorated CD4+CD25+ Tregs, which produced TGF-beta and maintained long-term tolerance. Full protection from T1D resulted from synergy between PD-L1 and CD4+CD25+ Tregs. Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • B7-1 Antigen / immunology
  • B7-1 Antigen / metabolism
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes / immunology
  • Coxsackievirus Infections / genetics
  • Coxsackievirus Infections / immunology*
  • Coxsackievirus Infections / metabolism
  • Coxsackievirus Infections / prevention & control*
  • Cytomegalovirus Infections / complications*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Female
  • Interferon-alpha / therapeutic use
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred NOD
  • Peptides / immunology
  • Peptides / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / immunology
  • Up-Regulation

Substances

  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Interferon-alpha
  • Interleukin-2 Receptor alpha Subunit
  • Membrane Glycoproteins
  • Peptides
  • Transforming Growth Factor beta