Continuum model of T-cell avidity: Understanding autoreactive and regulatory T-cell responses in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of insulin-secreting pancreatic β cells, leading to abolition of insulin secretion and onset of diabetes. Cytotoxic CD4+ and CD8+ T cells, activated by antigen presenting cells (APCs), are both implicated in disease onset and progression. Regulatory T cells (Tregs), on the other hand, play a leading role in regulating immunological tolerance and resistant homoeostasis in T1D by supressing effector T cells (Teffs). Recent data indicates that after activation, conventional Teffs transiently produce interleukin IL-2, a cytokine that acts as a growth factor for both Teffs and Tregs. Tregs suppress Teffs through IL-2 deprivation, competition and Teff conversion into inducible Tregs (iTregs). To investigate the interactions of these components during T1D progression, a mathematical model of T-cell dynamics is developed as a predictor of β-cell loss, with the underlying hypothesis that avidity of Teffs and Tregs, i.e., the binding affinity of T-cell receptors to peptide-major histocompatibility complexes on host cells, is continuum. The model is used to infer a set of criteria that determines susceptibility to T1D in high risk subjects. Our findings show that diabetes onset is guided by the absence of Treg-to-Teff dominance at specific high avidities, rather than over the whole range of avidity, and that the lack of overall dominance of Teffs-to-Tregs over time is the underlying cause of the “honeymoon period”, the remission phase observed in some T1D patients. The model also suggests that competition between Teffs and Tregs is more effective than Teff-induction into iTregs in suppressing Teffs, and that a prolonged full width at half maximum of IL-2 release is a necessary condition for curbing disease onset. Finally, the model provides a rationale for observing rapid and slow progressors of T1D based on modest heterogeneity in the kinetic parameters.