Herold, K. C., Vignali, D. A. A., Cooke, A. & Bluestone, J. A. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat. Rev. Immunol. 13, 243–256 (2013).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Doran, A. C., Yurdagul, A. & Tabas, I. Efferocytosis in health and disease. Nat. Rev. Immunol. 20, 254–267 (2020).

Article 
CAS 
PubMed 

Google Scholar
 

Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).

Article 
CAS 
PubMed 

Google Scholar
 

Park, M. D., Silvin, A., Ginhoux, F. & Merad, M. Macrophages in health and disease. Cell 185, 4259–4279 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Calderon, B. et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J. Exp. Med. 212, 1497–1512 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Brissova, M. et al. Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration. Cell Metab. 19, 498–511 (2014).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Riley, K. G. et al. Macrophages are essential for CTGF-mediated adult β-cell proliferation after injury. Mol. Metab. 4, 584–591 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Thai, L. M. et al. β-Cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFβ receptor signaling. iScience 26, 106477 (2023).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Banaei-Bouchareb, L. et al. Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J. Leukoc. Biol. 76, 359–367 (2004).

Article 
CAS 
PubMed 

Google Scholar
 

Oschilewski, U., Kiesel, U. & Kolb, H. Administration of silica prevents diabetes in BB-rats. Diabetes 34, 197–199 (1985).

Article 
CAS 
PubMed 

Google Scholar
 

Carrero, J. A. et al. Resident macrophages of pancreatic islets have a seminal role in the initiation of autoimmune diabetes of NOD mice. Proc. Natl Acad. Sci. USA 114, E10418–E10427 (2017).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Chen, D., Thayer, T. C., Wen, L. & Wong, F. S. Mouse models of autoimmune diabetes: the nonobese diabetic (NOD) mouse. Methods Mol. Biol. 2128, 87–92 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Calderon, B., Carrero, J. A. & Unanue, E. R. The central role of antigen presentation in islets of Langerhans in autoimmune diabetes. Curr. Opin. Immunol. 26, 32–40 (2014).

Article 
CAS 
PubMed 

Google Scholar
 

Mohan, J. F. et al. Imaging the emergence and natural progression of spontaneous autoimmune diabetes. Proc. Natl Acad. Sci. USA 114, E7776–E7785 (2017).

Zakharov, P. N., Hu, H., Wan, X. & Unanue, E. R. Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes. J. Exp. Med. 217, e20192362 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Pugliese, A. Autoreactive T cells in type 1 diabetes. J. Clin. Invest. 127, 2881–2891 (2017).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Delong, T. et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351, 711–714 (2016).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wan, X. et al. Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides. Nature 560, 107–111 (2018).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

DiLorenzo, T. P. & Serreze, D. V. The good turned ugly: immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice. Immunol. Rev. 204, 250–263 (2005).

Article 
CAS 
PubMed 

Google Scholar
 

Noble, J. A. & Erlich, H. A. Genetics of type 1 diabetes. Cold Spring Harb. Perspect. Med. 2, a007732 (2012).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Wang, Y. J. et al. Multiplexed in situ imaging mass cytometry analysis of the human endocrine pancreas and immune system in type 1 diabetes. Cell Metab. 29, 769–783 (2019).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Morioka, S. et al. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563, 714–718 (2018).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Tufan, T. et al. Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release. Nature 628, 408–415 (2024).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Hugues, S. et al. Tolerance to islet antigens and prevention from diabetes induced by limited apoptosis of pancreatic beta cells. Immunity 16, 169–181 (2002).

Article 
CAS 
PubMed 

Google Scholar
 

Boada-Romero, E., Martinez, J., Heckmann, B. L. & Green, D. R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 21, 398–414 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Turley, S., Poirot, L., Hattori, M., Benoist, C. & Mathis, D. Physiological β cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J. Exp. Med. 198, 1527–1537 (2003).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lenzen, S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51, 216–226 (2008).

Article 
CAS 
PubMed 

Google Scholar
 

Furman, B. L. Streptozotocin‐induced diabetic models in mice and rats. Curr. Protoc. 1, e78 (2021).

Article 
CAS 
PubMed 

Google Scholar
 

Ferris, S. T. et al. The islet-resident macrophage is in an inflammatory state and senses microbial products in blood. J. Exp. Med. 214, 2369–2385 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Brosseau, C., Colas, L., Magnan, A. & Brouard, S. CD9 tetraspanin: a new pathway for the regulation of inflammation? Front. Immunol. 9, 2316 (2018).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Sano, H. et al. Critical role of galectin-3 in phagocytosis by macrophages. J. Clin. Invest. 112, 389–397 (2003).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lemke, G. & Rothlin, C. V. Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8, 327–336 (2008).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lindsay, R. S. et al. MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites. J. Exp. Med. 218, e20200464 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Millet, A., Ledo, J. H. & Tavazoie, S. F. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains. Immunity 57, 153–170 (2024).

Article 
CAS 
PubMed 

Google Scholar
 

Jaitin, D. A. et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 178, 686–698 (2019).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).

Article 
CAS 
PubMed 

Google Scholar
 

Carrero, J. A., Calderon, B., Towfic, F., Artyomov, M. N. & Unanue, E. R. Defining the transcriptional and cellular landscape of type 1 diabetes in the NOD mouse. PLoS ONE 8, e59701 (2013).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Calderon, B., Carrero, J. A., Miller, M. J. & Unanue, E. R. Cellular and molecular events in the localization of diabetogenic T cells to islets of Langerhans. Proc. Natl Acad. Sci. USA 108, 1561–1566 (2011).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Katz, J. D., Wang, B., Haskins, K., Benoist, C. & Mathis, D. Following a diabetogenic T cell from genesis through pathogenesis. Cell 74, 1089–1100 (1993).

Article 
CAS 
PubMed 

Google Scholar
 

Gonzalez, A. et al. Genetic control of diabetes progression. Immunity 7, 873–883 (1997).

Article 
CAS 
PubMed 

Google Scholar
 

Trefzer, A. et al. Dynamic adoption of anergy by antigen-exhausted CD4+ T cells. Cell Rep. 34, 108748 (2021).

Article 
CAS 
PubMed 

Google Scholar
 

Titcombe, P. J., Silva Morales, M., Zhang, N. & Mueller, D. L. BATF represses BIM to sustain tolerant T cells in the periphery. J. Exp. Med. 220, e20230183 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Kalekar, L. A. et al. CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat. Immunol. 17, 304–314 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Price, J. D., Hotta-Iwamura, C., Zhao, Y., Beauchamp, N. M. & Tarbell, K. V. DCIR2+ cDC2 DCs and Zbtb32 restore CD4+ T-cell tolerance and inhibit diabetes. Diabetes 64, 3521–3531 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Shin, H. M. et al. Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory. PLoS Pathog. 13, e1006544 (2017).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Alroy, I., Towers, T. L. & Freedman, L. P. Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol. Cell. Biol. 15, 5789–5799 (1995).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Martinez, R. J. et al. Arthritogenic self-reactive CD4+ T cells acquire an FR4hiCD73hi anergic state in the presence of Foxp3+ regulatory T cells. J. Immunol. 188, 170–181 (2012).

Article 
CAS 
PubMed 

Google Scholar
 

Browaeys, R., Saelens, W. & Saeys, Y. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat. Methods 17, 159–162 (2020).

Article 
CAS 
PubMed 

Google Scholar
 

Nackiewicz, D. et al. Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet insulin-like growth factor-1. iScience 23, 100775 (2020).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Shapiro, M. R. et al. Insulin-like growth factor dysregulation both preceding and following type 1 diabetes diagnosis. Diabetes 69, 413–423 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Han, C. Z. et al. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature 539, 570–574 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Mallol, C. et al. AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice. Mol. Metab. 6, 664–680 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Finegood, D. T., Scaglia, L. & Bonner-Weir, S. Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44, 249–256 (1995).

Article 
CAS 
PubMed 

Google Scholar
 

Scaglia, L., Cahill, C. J., Finegood, D. T. & Bonner-Weir, S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138, 1736–1741 (1997).

Article 
CAS 
PubMed 

Google Scholar
 

Trudeau, J. D. et al. Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49, 1–7 (2000).

Article 
CAS 
PubMed 

Google Scholar
 

Kassem, S. A., Ariel, I., Thornton, P. S., Scheimberg, I. & Glaser, B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49, 1325–1333 (2000).

Article 
CAS 
PubMed 

Google Scholar
 

Ciecko, A. E. et al. Heterogeneity of islet-infiltrating IL-21+ CD4 T cells in a mouse model of type 1 diabetes. J. Immunol. 210, 935–946 (2023).

Article 
CAS 
PubMed 

Google Scholar
 

Foda, B. M. et al. The CD137 ligand is important for type 1 diabetes development but dispensable for the homeostasis of disease-suppressive CD137+FOXP3+ regulatory CD4 T cells. J. Immunol. 204, 2887–2899 (2020).

Article 
CAS 
PubMed 

Google Scholar
 

Mohan, J. F., Calderon, B., Anderson, M. S. & Unanue, E. R. Pathogenic CD4+ T cells recognizing an unstable peptide of insulin are directly recruited into islets bypassing local lymph nodes. J. Exp. Med. 210, 2403–2414 (2013).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Goudy, K. S. et al. Systemic overexpression of IL-10 induces CD4+CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion. J. Immunol. 171, 2270–2278 (2003).

Article 
CAS 
PubMed 

Google Scholar
 

Kolberg, L., Raudvere, U., Kuzmin, I., Vilo, J. & Peterson, H. gprofiler2—an R package for gene list functional enrichment analysis and namespace conversion toolset g:Profiler. F1000Research 9, ELIXIR-709 (2020).

Wu, T. et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).

CAS 
PubMed 
PubMed Central 

Google Scholar
 

Zinselmeyer, B. H. et al. The resident macrophages in murine pancreatic islets are constantly probing their local environment, capturing beta cell granules and blood particles. Diabetologia 61, 1374–1383 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Zhu, A., Ibrahim, J. G. & Love, M. I. Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. Bioinformatics 35, 2084–2092 (2019).

Article 
CAS 
PubMed 

Google Scholar
 

Blighe, K. et al. EnhancedVolcano: publication-ready volcano plots with enhanced colouring and labeling. https://doi.org/10.18129/B9.BIOC.ENHANCEDVOLCANO (Bioconductor, 2018).

Zhang, Y., Parmigiani, G. & Johnson, W. E. ComBat-seq: batch effect adjustment for RNA-seq count data. NAR Genom. Bioinform. 2, lqaa078 (2020).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).

Article 
PubMed 
PubMed Central 

Google Scholar