T cells in type 1 diabetes: mechanisms of β-cell autoimmunity, innate-adaptive immune crosstalk, and translational immunotherapy
TL;DR
Recent advances in the immunobiology of T cells in T1D are synthesized, emphasizing their functional interplay with innate immune cells, tracing the path from mechanistic discovery to clinical translation, and highlighting future directions for precision immunotherapy.
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which immune responses drive the destruction of insulin-producing pancreatic β-cells, ultimately resulting in lifelong insulin dependence. Although T cells are central mediators of β-cell autoimmunity, growing evidence shows that innate immune cells, including dendritic cells, macrophages, and natural killer (NK) cells, play essential roles in initiating, shaping, and sustaining pathogenic adaptive responses within the islet microenvironment. Both CD4 + helper and CD8 + cytotoxic T lymphocytes contribute to β-cell injury through the production of inflammatory cytokines, direct cytotoxicity, and disruption of self-tolerance. At the same time, regulatory T cells exhibit reduced numbers and/or impaired suppressive function, thereby further accelerating autoimmune progression. Recent advances in animal models, single-cell transcriptomics, spatial immune profiling, and T cell receptor sequencing have refined our understanding of autoreactive repertoires, antigen specificity, and bidirectional crosstalk between innate and adaptive immune compartments. At the translational level, immune signatures are emerging as tools for disease prediction and patient stratification, while therapeutic strategies ranging from anti-CD3 monoclonal antibodies to tolerogenic vaccines and adoptive Treg therapies are moving from preclinical development into clinical evaluation. The clinical success of teplizumab as the first disease-modifying therapy for T1D reinforces the value of targeting immune pathways, but durable remission across diverse patient groups remains a major challenge. This review synthesizes recent advances in the immunobiology of T cells in T1D, emphasizing their functional interplay with innate immune cells, tracing the path from mechanistic discovery to clinical translation, and highlighting future directions for precision immunotherapy.