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Related Experiment Videos

(Pro)insulin-specific regulatory T cells.

Leonard C Harrison1, Natasha R Solly, Nathan R Martinez

  • 1Autoimmunity and Transplantation Division, The Walter & Eliza Hall Institute of Medical Research, PO The Royal Melbourne Hospital, Parkville, 3050 Victoria, Australia.

Novartis Foundation Symposium
|November 12, 2003
PubMed
Summary
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Mucosal insulin administration induces regulatory T cells (Treg) to prevent type 1 diabetes in mice. Extrathymic T cells are crucial for this immune regulation, highlighting early environmental influences.

Area of Science:

  • Immunology
  • Endocrinology
  • Autoimmunity

Background:

  • Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing beta cells.
  • Regulatory T cells (Treg) play a critical role in maintaining immune tolerance and preventing autoimmune diseases.
  • The non-obese diabetic (NOD) mouse is a widely used model for studying type 1 diabetes.

Purpose of the Study:

  • To investigate the induction of regulatory anti-diabetogenic T cells (Treg) via mucosal administration of insulin or proinsulin peptides in NOD mice.
  • To elucidate the role of specific T cell subsets, particularly CD8+ alpha(alpha) TCR gamma(delta) T cells, in preventing autoimmune diabetes.
  • To understand the influence of the thymus and early environmental exposure on the development of regulatory T cells.

Main Methods:

Related Experiment Videos

  • Mucosal administration of insulin or proinsulin peptides to NOD mice.
  • Naso-respiratory delivery of insulin to bypass degradation.
  • Neonatal thymectomy (NTX) to assess the role of the thymus.
  • Analysis of T cell populations (CD8+ alpha(alpha) TCR gamma(delta) T cells) and cytokine production (IL-10) in pancreatic lymph nodes.
  • Reconstitution of NTX-NOD mice with specific T cell subsets.

Main Results:

  • Naso-respiratory insulin induced CD8+ alpha(alpha) TCR gamma(delta) T(reg), while other peptides induced CD4+ T(regs).
  • Insulin administration increased CD8+ gamma(delta) T cells expressing IL-10 in pancreatic lymph nodes.
  • Neonatal thymectomy accelerated diabetes and impaired the maturation of extrathymic CD8+ alpha(alpha) TCR gamma(delta) IEL.
  • Regulatory T cell induction by naso-respiratory insulin was abolished in NTX-NOD mice.
  • Reconstitution with CD8+ alpha(alpha) TCR gamma(delta) T cells prevented diabetes in NTX-NOD mice.

Conclusions:

  • Extrathymic-derived CD8+ alpha(alpha) TCR gamma(delta) T cells play a critical role in preventing autoimmune diabetes.
  • These regulatory T cells are likely induced by early exposure to environmental factors, such as insulin in maternal milk.
  • The thymus influences the development and function of these extrathymic regulatory T cells.
  • Findings suggest an immunoregulatory role for extrathymic-derived IELs conditioned by early environmental exposure.