Mechanisms That Regulate Peripheral Immune Responses to Control Organ-Specific Autoimmunity

Gerard F Hoyne

doi:10.1155/2011/294968

Abstract

The immune system must balance the need to maintain a diverse repertoire of lymphocytes to be able to fight infection with the need to maintain tolerance to self-proteins. The immune system places strict regulation over the ability of T cells to produce the major T cell growth factor interleukin 2 as this cytokine can influence a variety of immune outcomes. T cells require the delivery of two signals, one through the antigen receptor and a second through the costimulatory receptor CD28. The immune system uses a variety of E3 ubiquitin ligases to target signaling proteins that function downstream of the TCR and CD28 receptors. Mutations in these E3 ligases can lead to a breakdown in immune tolerance and development of autoimmunity. This paper will examine the role of a range of E3 ubiquitin ligases and signaling pathways that influence the development of T-cell effector responses and the development of organ-specific autoimmune diseases such as type 1 diabetes.

Highlights

The immune system has evolved to protect the body from infectious pathogens through both innate and adaptive immune responses
Ligation of TCR on T cells in the absence of CD28 costimulation leads to the development of clonal anergy which is characterized by the failure to activate the MAPK, PI3 kinase (PI3K)/AKT, and the IKK pathways and results in reduced activity of the nuclear factors AP-1 and NF-κB and deficient IL-2 gene transcription, but there is elevated NFAT signalling in anergic cells [5]
The development of Type 1 diabetes (T1D) is caused by the breakdown of immune tolerance to islet-specific antigens in the pancreas

Summary

Introduction

The immune system has evolved to protect the body from infectious pathogens through both innate and adaptive immune responses. Type 1 diabetes (T1D) is an example of an organ-specific autoimmune disease caused by the breakdown in tolerance in both CD4+ and CD8+ T cells and B cells that express antigen receptors specific for proteins derived from the islets of Langerhans in the pancreas. Type 1 diabetes arises as a result of a breakdown of tolerance in islet reactive T cells. This leads to immunological destruction of the pancreatic beta cells and loss of insulin secretion that is mediated by CD4+ and CD8+ T cells [6]. It was originally thought that clonal anergy and regulatory T cells were entirely distinct mechanisms that are used to control peripheral immune responses. In addition I will examine how signaling through the AKT/mammalian target of rapamycin (mTOR) pathway has important roles in balancing the choice between immunity and suppression

T-Cell Activation and Generation of Effector Responses

Clonal Anergy

Regulation of T-Cell Activation by E3 Ubiquitin Ligases

Cblb and Itch in Regulatory T Cell Development

Regulation of T-Cell Activation by Sensing the Environment

Concluding Remarks