The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the “single disease” approach appears untenable, as does the notion of individualizing each single patient’s care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4⁺FOXP3⁺Helios⁺ thymic-derived Tregs and CD4⁺FOXP3⁺Helios⁻ T cells, followed by comparison with CD4⁺FOXP3⁻Helios⁻ T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4⁺CD25⁺CD127^lo/− T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226⁺TIGIT⁻ population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.

SARS-CoV-2–specific memory cells persist in multiple sites months after infection, particularly in lungs and associated lymph nodes.

The adaptive immune repertoire plays a critical role in type 1 diabetes (T1D) pathogenesis. However, efforts to characterize B cell and T cell receptor (TCR) profiles in T1D subjects have been largely limited to peripheral blood sampling and restricted to known antigens. To address this, we collected pancreatic draining lymph nodes (pLN), “irrelevant” nonpancreatic draining lymph nodes, peripheral blood mononuclear cells (PBMC), and splenocytes from T1D subjects ( n = 18) and control donors ( n = 9) as well as pancreatic islets from 1 T1D patient; from these tissues, we collected purified CD4 ⁺ conventional T cells (Tconv), CD4 ⁺ Treg, CD8 ⁺ T cells, and B cells. By conducting high-throughput immunosequencing of the TCR β chain ( TRB ) and B cell receptor (BCR) immunoglobulin heavy chain ( IGH ) on these samples, we sought to analyze the molecular signature of the lymphocyte populations within these tissues and of T1D. Ultimately, we observed a highly tissue-restricted CD4 ⁺ repertoire, while up to 24% of CD8 ⁺ clones were shared among tissues. We surveyed our data set for previously described proinsulin- and glutamic acid decarboxylase 65–reactive (GAD65-reactive) receptors, and interestingly, we observed a TRB with homology to a known GAD65-reactive TCR (clone GAD4.13) present in 7 T1D donors (38.9%), representing >25% of all productive TRB within Tconv isolated from the pLN of 1 T1D subject. These data demonstrate diverse receptor signatures at the nucleotide level and enriched autoreactive clones at the amino acid level, supporting the utility of coupling immunosequencing data with knowledge of characterized autoreactive receptors.

Follicular helper T (T_FH) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating T_FHcells would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of T_FHcells in lupus-prone mice. However, this inhibition has little effect on the production of T-cell-dependent antibodies following immunization with an exogenous antigen or on the frequency of virus-specific T_FHcells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces both immunization-induced and autoimmune T_FHcells and humoral responses. Solute transporter gene signature suggests different glucose and amino acid fluxes between autoimmune T_FHcells and exogenous antigen-specific T_FHcells. Thus, blocking glucose metabolism may provide an effective therapeutic approach to treat systemic autoimmunity by eliminating autoreactive T_FHcells while preserving protective immunity against pathogens.

Technological advancements in blood glucose monitoring and therapeutic insulin administration have improved the quality of life for people with type 1 diabetes. However, these efforts fall short of replicating the exquisite metabolic control provided by native islets. We examine the integrated advancements in islet cell replacement and immunomodulatory therapies that are coalescing to enable the restoration of endogenous glucose regulation. We highlight advances in stem cell biology and graft site design, which offer innovative sources of cellular material and improved engraftment. We also cover cutting-edge approaches for preventing allograft rejection and recurrent autoimmunity. These insights reflect a growing understanding of type 1 diabetes etiology, β cell biology, and biomaterial design, together highlighting therapeutic opportunities to durably replace the β cells destroyed in type 1 diabetes.