Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response

Abstract

Inflammation is typically induced in response to a microbial infection. The release of proinflammatory cytokines enhances the stimulatory capacity of antigen-presenting cells, as well as recruits adaptive and innate immune effectors to the site of infection. Once the microbe is cleared, inflammation is resolved by various mechanisms to avoid unnecessary tissue damage. Autoimmunity arises when aberrant immune responses target self-tissues causing inflammation. In type 1 diabetes (T1D), T cells attack the insulin producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by in part altering central and peripheral tolerance inducing events. This results in the development and expansion of β cell-specific effector T cells (Teff) which mediate islet inflammation. Unlike protective immunity where inflammation is terminated, autoimmunity is sustained by chronic inflammation. In this review, we will highlight the key events which initiate and sustain T cell-driven pancreatic islet inflammation in nonobese diabetic mice and in human T1D. Specifically, we will discuss: (i) dysregulation of thymic selection events, (ii) the role of intrinsic and extrinsic factors that enhance the expansion and pathogenicity of Teff, (iii) defects which impair homeostasis and suppressor activity of FoxP3-expressing regulatory T cells, and (iv) properties of β cells which contribute to islet inflammation.

Keywords: T cells; autoimmunity; immunoregulation; inflammation; type 1 diabetes.

Figure 1

Dysregulated thymic and peripheral events culminate in chronic islet inflammation. In general, overt diabetes results from the gradual loss of functional insulin producing β cells due to the inflammatory environment driven by infiltrating self-reactive T cells and antigen-presenting cell (APC). Although β cell-specific T cell clones are detected in both healthy and type 1 diabetes (T1D) susceptible individuals, a number of factors promote T1D development in the latter population. Decreased efficiency of negative selection in the thymus, either due to altered tissue-specific antigen expression or due to T cell receptor (TCR) signaling, allows for the increased escape of β cell-specific T cell clones into the periphery. In addition, β cell-specific Foxp3⁺Treg development may also be suboptimal due to dysregulation of TCR signaling. In the periphery, β cell-specific T cells are stimulated in the pancreatic lymph nodes (pLN) by APC derived from the islets, leading to effector T cell (Teff) differentiation. These pathogenic Teff then infiltrate the islets and drive inflammation leading to reduced β cell function and/or survival. Not all islets are infiltrated potentially due to an immature phenotype and reduced autoantigen expression by β cells. Ongoing islet inflammation also leads to the generation of neoautoantigens either directly in β cells or during antigen processing by APC. The presentation of neoautoantigens within the pLN promotes the activation and expansion of additional Teff pools. These events amplify and drive a chronic state of islet inflammation leading to impaired functional β cell mass and clinical onset of T1D.