Diabetes is associated with increased mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2), the key entry factor for SARS-CoV-2 infection. Specifically, we analyzed five public scRNA-seq pancreas datasets and performed fluorescence in situ hybridization, western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) cases. These in silico and ex vivo analyses demonstrated prominent expression of ACE2 in pancreatic ductal epithelium and microvasculature, but we found rare endocrine cell expression at the mRNA level. Pancreata from individuals with COVID-19 demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression that was primarily limited to ducts. These results suggest SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, is an unlikely central pathogenic feature of COVID-19-related diabetes.

The human body at cellular resolution: the NIH Human Biomolecular Atlas Program HuBMAP consortium* Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at singlecell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions. t he human body is an incredible machine. Trillions of cells, organized across an array of spatial scales and a multitude of functional states, contribute to a symphony of physiology. While we broadly know how cells are organized in most tissues, a comprehensive understanding of the cellular and molecular states and interactive networks resident in the tissues and organs, from organizational and functional perspectives, is lacking. The specific three-dimensional organization of different cell types, together with the effects of cell-cell and cell-matrix interactions in their natural milieu, have a profound impact on normal function, natural ageing, tissue remodelling, and disease progression in different tissues and organs. Recently, new technologies have enabled the molecular characterization of a multitude of cell types 1-4 and mapping of their spatial relationships in complex tissues at unprecedented scale and single-cell resolution. These advances create the opportunity to build a high-resolution atlas of three-dimensional maps of human tissues and organs. HuBMAP (https://commonfund.nih.gov/hubmap) is an NIHsponsored program with the goals of developing an open framework and technologies for mapping the human body at cellular resolution as well as generating foundational maps for several tissues obtained from normal individuals across a wide range of ages. A previous NIH-sponsored project, GTEx 5 , examined DNA variants and bulk tissue expression patterns across approximately a thousand individuals, but HuBMAP is a distinct project focused on generating molecular maps that are spatially resolved at the single-cell level but using samples from a more limited number of people. To achieve these goals, HuBMAP has been designed as a cohesive and collaborative organization, with a culture of openness and sharing using team science-based approaches 6. The HuBMAP Consortium (https://hubmapconsortium.org/) will actively work with other ongoing initiatives including the Human Cell Atlas 7 , Human Protein Atlas 8 , LIfeTime (https://lifetime-fetflagship.eu/), and related NIH-funded consortia that are mapping specific organs (including the brain 9 , lungs (https://www.lungmap.net/), kidney (https...

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With the conceptual advance some four decades ago that type 1 diabetes (T1D) represents an autoimmune disease, hope emerged that immune-based therapies would quickly evolve as a means to prevent and reverse the disorder. However, despite dozens of clinical trials seeking to achieve that purpose, the goal remains unfulfilled, at least in a pragmatic form. With the benefit of hindsight, multiple reasons are likely to account for this unfortunate situation, and several stand out: failure to appreciate disease heterogeneity; inappropriate utilization of and insight from rodent models of disease; inadequacies in addressing the immunologic and metabolic contributions to the disease; suboptimal trial designs; and lack of a clear understanding of the disorder's pathogenesis. This review conveys how recent knowledge gains in these areas, combined with efforts related to disease staging and emerging mechanistic data from clinical trials, provide cautious optimism that an immune-based means to prevent the loss of β-cells in T1D will emerge into clinical practice.

The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt β-cell destruction. We generated human Tregs expressing a high-affinity GAD555–567-reactive TCR (clone R164), as well as the lower affinity clone 4.13 specific for the same peptide. We demonstrated that de novo Treg avatars potently suppress antigen-specific and bystander responder T-cell (Tresp) proliferation in vitro in a process that requires Treg activation (P < 0.001 versus unactivated Tregs). When Tresp were also glutamic acid decarboxylase (GAD)-reactive, the high-affinity R164 Tregs exhibited increased suppression (P < 0.01) with lower Tresp-division index (P < 0.01) than the lower affinity 4.13 Tregs. These data demonstrate the feasibility of rapid expansion of antigen-specific Tregs for applications in attenuating β-cell autoimmunity and emphasize further opportunities for engineering cellular specificities, affinities, and phenotypes to tailor Treg activity in adoptive cell therapies for the treatment of type 1 diabetes.