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.
Highlights
T cell-driven autoimmune diseases are heterogeneous and complex, typically leading to chronic organ-specific inflammation and tissue damage
Multiple immune defects contribute to a failure of b cellspecific self-tolerance which impacts the function of various immune effector cells, including T cells
Genetic variants associated with increased Type 1 diabetes (T1D) susceptibility have been linked to the generation of self-reactive T cell receptor (TCR) and dysregulated TCR signaling events
Summary
T cell-driven autoimmune diseases are heterogeneous and complex, typically leading to chronic organ-specific inflammation and tissue damage. Aberrant immunoregulation contributes to the differentiation and expansion of pathogenic Teff in T1D [67, 68] Both natural and induced immunoregulatory CD4+ T cells expressing the forkhead box P3 protein transcription factor (nFoxp3+Treg and iFoxp3+Treg, respectively) play a critical role in suppressing autoimmunity [69,70,71,72,73,74,75,76]. We will discuss how key TCR signaling events in human T1D patients and the NOD mouse alters T cell development in the thymus that favors an autoreactive TCR repertoire, and how dysregulation of TCR signaling in the periphery imprints a proinflammatory phenotype in b cellspecific Teff that drives pancreatic islet damage
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