Autoreactive T Cell Responses Show Proinflammatory Polarization in Diabetes but a Regulatory Phenotype in Health

J Clin Invest. 2004 Feb;113(3):451-63. doi: 10.1172/JCI19585.

Abstract

According to the quality of response they mediate, autoreactive T cells recognizing islet beta cell peptides could represent both disease effectors in the development of type 1 diabetes (T1DM) and directors of tolerance in nondiabetic individuals or those undergoing preventative immunotherapy. A combination of the rarity of these cells, inadequate technology, and poorly defined epitopes, however, has hampered examination of this paradigm. We have identified a panel of naturally processed islet epitopes by direct elution from APCs bearing HLA-DR4. Employing these epitopes in a sensitive, novel cytokine enzyme-linked immunosorbent spot assay, we show that the quality of autoreactive T cells in patients with T1DM exhibits extreme polarization toward a proinflammatory Th1 phenotype. Furthermore, we demonstrate that rather than being unresponsive, the majority of nondiabetic, HLA-matched control subjects also manifest a response against islet peptides, but one that shows extreme T regulatory cell (Treg, IL-10-secreting) bias. We conclude that development of T1DM depends on the balance of autoreactive Th1 and Treg cells, which may be open to favorable manipulation by immune intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Autoimmunity / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • HLA-DR4 Antigen / metabolism
  • Humans
  • Inflammation / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-4 / metabolism
  • Peptides / metabolism
  • Proinsulin / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Autoantibodies
  • HLA-DR4 Antigen
  • ICA512 autoantibody
  • Peptides
  • Interleukin-4
  • Interferon-gamma
  • Proinsulin