The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes

Abstract

T cell receptor (TCR) signaling influences multiple aspects of CD4⁺ and CD8⁺ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.

Keywords: T cell differentiation; T cell receptor (TCR) signaling; autoimmunity; diabetes; immunoregulation.

Figure 1

Dysregulated central tolerance impacts T cell receptor (TCR) signaling and establishes a T cell repertoire with increased type 1 diabetes (T1D) susceptibility. (A) In the thymus cortex, double positive thymocytes (DP) engage cortical thymic epithelial cell (cTEC) through TCR/peptide-MHC complexes (pMHC) interactions. Self-peptides are processed via the thymoproteasome and lysosomal proteases and displayed by MHC I and II molecules expressed by cTEC. DP recognizing these self-peptides receive survival signals, differentiate into CD4⁺ or CD8⁺ single positive thymocytes (SP) and migrate to the medulla. Alternatively, DP thymocytes incapable of transmitting TCR mediated survival signals die due to neglect. In the medulla, SP interact with mTEC or DC. Medullary TEC (mTEC) express a variety of tissue-specific antigens (TSA) such as insulin under the control of transcription factors autoimmune regulator (AIRE) and forebrain expressed zinc finger 2 (Fezf2). TSA are processed and presented on the MHC of mTEC, which can be acquired by DC by various mechanisms. SP with high TCR affinity for self-antigens are deleted through apoptosis, whereas SP exhibiting low TCR self-reactivity become naïve T cells. A fraction of CD4⁺ SP thymocytes with intermediate to high affinity differentiate into nFoxp3⁺Treg. Surviving SP exit the thymus and comprise the peripheral TCR repertoire. Red thick arrow: high TCR/pMHC affinity. Red thin arrow: intermediate TCR/pMHC affinity. Black arrow: low TCR/pMHC affinity. (B) Deficiency in self-peptide expression or processing by cTEC reduces TCR repertoire diversity and potentially increases susceptibility to β cell autoimmunity. Reduced expression and presentation of β cell-specific peptides by mTEC and other thymic APC limits: 1) negative selection leading to escape of an increased frequency of β cell-specific T cells with increased affinity/avidity, as well as impaired development of β cell-specific Foxp3⁺Treg. AEP, Asparaginyl endopeptidase.

Figure 2

Dysregulated peripheral tolerance and the role of T cell receptor (TCR) signaling in type 1 diabetes (T1D) pathogenesis. (A) Upon interacting with antigen presenting cell (APC), peripheral T cells differentiate into distinct subsets through activation of specific sets of transcription factors based on TCR signal strength (signal 1), co-stimulatory molecule engagement (signal 2) and the cytokine environment (signal 3). Low TCR signaling favors differentiation of adaptive regulatory T cell subsets such as iFoxp3⁺Treg. Strong and/or persistent TCR signaling favors differentiation of Th1, Tfh, and Th17 subsets. Increased TCR signaling in T1D aids in disrupting the balance between pro inflammatory and regulatory immune responses. (B) In T1D, increased affinity for and/or prolonged interaction with β cell peptide-MHC complexes results in elevated TCR signaling. Elevated TCR signaling coupled with signals derived via co-stimulation and proinflammatory cytokines, promotes differentiation of pathogenic Teff such as IFNγ-producing Th1 cells and cytolytic Tc1 cells, that migrate into the islets and mediate β cell destruction. Chronic TCR signaling normally leads to T cell exhaustion and dampened Teff function. However, elevated levels of IL-21 rescue Teff from terminal exhaustion to maintain β cell destruction. Tmem contribute to maintenance of β cell autoimmunity by providing a source of chronic proinflammatory cytokines upon antigen stimulation. Red TCR (high TCR signal). Green TCR (low TCR signal).