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Congenic mapping identifies a novel Idd9 subregion regulating type 1 diabetes in NOD mice

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Abstract

Type 1 diabetes (T1D) results from complex interactions between genetic and environmental factors. The nonobese diabetic (NOD) mouse develops spontaneous T1D and has been used extensively to study the genetic control of this disease. T1D is suppressed in NOD mice congenic for the C57BL/10 (B10)-derived Idd9 resistance region on chromosome 4. Previous studies conducted by other investigators have identified four subregions (Idd9.1, Idd9.2, Idd9.3, and Idd9.4) where B10-derived genes suppress T1D development in NOD mice. We independently generated and characterized six congenic strains containing B10-derived intervals that partially overlap with the Idd9.1 and Idd9.4 regions. T1D incidence studies have revealed a new B10-derived resistance region proximal to Idd9.1. Our results also indicated that a B10-derived gene(s) within the Idd9.4 region suppressed the diabetogenic activity of CD4 T cells and promoted CD103 expression on regulatory T cells indicative of an activated phenotype. In addition, we suggest the presence of a B10-derived susceptibility gene(s) in the Idd9.1/Idd9.4 region. These results provide additional information to improve our understanding of the complex genetic control by the Idd9 region.

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References

  • Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, Julier C, Morahan G, Nerup J, Nierras C, Plagnol V, Pociot F, Schuilenburg H, Smyth DJ, Stevens H, Todd JA, Walker NM, Rich SS (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berry GJ, Frielle C, Brucklacher RM, Salzberg AC, Waldner H (2015) Identifying type 1 diabetes candidate genes by DNA microarray analysis of islet-specific CD4 + T cells. Genomics data 5:184–188

    Article  PubMed  PubMed Central  Google Scholar 

  • Bettini M, Vignali DA (2009) Regulatory T cells and inhibitory cytokines in autoimmunity. Curr Opin Immunol 21:612–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brodnicki TC, Fletcher AL, Pellicci DG, Berzins SP, McClive P, Quirk F, Webster KE, Scott HS, Boyd RL, Godfrey DI, Morahan G (2005) Localization of Idd11 is not associated with thymus and nkt cell abnormalities in NOD mice. Diabetes 54:3453–3457

    Article  CAS  PubMed  Google Scholar 

  • Cannons JL, Chamberlain G, Howson J, Smink LJ, Todd JA, Peterson LB, Wicker LS, Watts TH (2005) Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. J Autoimmun 25:13–20

    Article  CAS  PubMed  Google Scholar 

  • Chen YG, Scheuplein F, Osborne MA, Tsaih SW, Chapman HD, Serreze DV (2008) Idd9/11 genetic locus regulates diabetogenic activity of CD4 T-cells in nonobese diabetic (NOD) mice. Diabetes 57:3273–3280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YG, Cabrera SM, Jia S, Kaldunski ML, Kramer J, Cheong S, Geoffrey R, Roethle MF, Woodliff JE, Greenbaum CJ, Wang X, Hessner MJ (2014) Molecular signatures differentiate immune states in type 1 diabetic families. Diabetes 63:3960–3973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christianson SW, Shultz LD, Leiter EH (1993) Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 42:44–55

    Article  CAS  PubMed  Google Scholar 

  • Chung B, Stadion M, Schulz N, Jain D, Scherneck S, Joost HG, Schurmann A (2015) The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice. Diabetologia 58:2403–2413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diana J, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, Lehuen A (2013) Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med 19:65–73

    Article  CAS  PubMed  Google Scholar 

  • DiLorenzo TP, Graser RT, Ono T, Christianson GJ, Chapman HD, Roopenian DC, Nathenson SG, Serreze DV (1998) Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement. Proc Natl Acad Sci U S A 95:12538–12543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Driver JP, Serreze DV, Chen YG (2011) Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease. Semin Immunopathol 33:67–87

    Article  CAS  PubMed  Google Scholar 

  • Ferreira RC, Guo H, Coulson RM, Smyth DJ, Pekalski ML, Burren OS, Cutler AJ, Doecke JD, Flint S, McKinney EF, Lyons PA, Smith KG, Achenbach P, Beyerlein A, Dunger DB, Clayton DG, Wicker LS, Todd JA, Bonifacio E, Wallace C, Ziegler AG (2014) A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes. Diabetes 63:2538–2550

    Article  PubMed  PubMed Central  Google Scholar 

  • Garg G, Tyler JR, Yang JH, Cutler AJ, Downes K, Pekalski M, Bell GL, Nutland S, Peakman M, Todd JA, Wicker LS, Tree TI (2012) Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4 + CD25+ regulatory T cell function. J Immunol 188:4644–4653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregg RK, Jain R, Schoenleber SJ, Divekar R, Bell JJ, Lee HH, Yu P, Zaghouani H (2004) A sudden decline in active membrane-bound TGF-beta impairs both T regulatory cell function and protection against autoimmune diabetes. J Immunol 173:7308–7316

    Article  CAS  PubMed  Google Scholar 

  • Hamilton-Williams EE, Wong SB, Martinez X, Rainbow DB, Hunter KM, Wicker LS, Sherman LA (2010) Idd9.2 and Idd9.3 protective alleles function in CD4+ T-cells and nonlymphoid cells to prevent expansion of pathogenic islet-specific CD8+ T-cells. Diabetes 59:1478–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamilton-Williams EE, Rainbow DB, Cheung J, Christensen M, Lyons PA, Peterson LB, Steward CA, Sherman LA, Wicker LS (2013) Fine mapping of type 1 diabetes regions Idd9.1 and Idd9.2 reveals genetic complexity. Mammalian genome: official journal of the International Mammalian Genome Society 24:358–375

    Article  CAS  Google Scholar 

  • Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, Debes GF, Lauber J, Frey O, Przybylski GK, Niesner U, de la Rosa M, Schmidt CA, Brauer R, Buer J, Scheffold A, Hamann A (2004) Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med 199:303–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeker LT, Bour-Jordan H, Bluestone JA (2012) Breakdown in peripheral tolerance in type 1 diabetes in mice and humans. Cold Spring Harb Perspect Med 2:a007807

    Article  PubMed  PubMed Central  Google Scholar 

  • Kachapati K, Adams DE, Wu Y, Steward CA, Rainbow DB, Wicker LS, Mittler RS, Ridgway WM (2012) The B10 Idd9.3 locus mediates accumulation of functionally superior CD137+ regulatory T cells in the nonobese diabetic type 1 diabetes model. J Immunol 189:5001–5015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kallionpaa H, Elo LL, Laajala E, Mykkanen J, Ricano-Ponce I, Vaarma M, Laajala TD, Hyoty H, Ilonen J, Veijola R, Simell T, Wijmenga C, Knip M, Lahdesmaki H, Simell O, Lahesmaa R (2014) Innate immune activity is detected prior to seroconversion in children with HLA-conferred type 1 diabetes susceptibility. Diabetes 63:2402–2414

    Article  PubMed  Google Scholar 

  • Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI (2005) Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 54:92–99

    Article  CAS  PubMed  Google Scholar 

  • Long SA, Cerosaletti K, Bollyky PL, Tatum M, Shilling H, Zhang S, Zhang ZY, Pihoker C, Sanda S, Greenbaum C, Buckner JH (2010) Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects. Diabetes 59:407–415

    Article  CAS  PubMed  Google Scholar 

  • Lyons PA, Hancock WW, Denny P, Lord CJ, Hill NJ, Armitage N, Siegmund T, Todd JA, Phillips MS, Hess JF, Chen SL, Fischer PA, Peterson LB, Wicker LS (2000) The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137. Immunity 13:107–115

    Article  CAS  PubMed  Google Scholar 

  • McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, Hoffmuller U, Baron U, Olek S, Bluestone JA, Brusko TM (2011) Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 186:3918–3926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Onengut-Gumuscu S, Chen WM, Burren O, Cooper NJ, Quinlan AR, Mychaleckyj JC, Farber E, Bonnie JK, Szpak M, Schofield E, Achuthan P, Guo H, Fortune MD, Stevens H, Walker NM, Ward LD, Kundaje A, Kellis M, Daly MJ, Barrett JC, Cooper JD, Deloukas P, Todd JA, Wallace C, Concannon P, Rich SS (2015) Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet 47:381–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R (2005) Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4 + CD25+ regulatory T cells during autoimmune diabetes. J Exp Med 201:1333–1346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scherneck S, Nestler M, Vogel H, Bluher M, Block MD, Berriel Diaz M, Herzig S, Schulz N, Teichert M, Tischer S, Al-Hasani H, Kluge R, Schurmann A, Joost HG (2009) Positional cloning of zinc finger domain transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL. PLoS Genet 5:e1000541

    Article  PubMed  PubMed Central  Google Scholar 

  • Serra P, Amrani A, Yamanouchi J, Han B, Thiessen S, Utsugi T, Verdaguer J, Santamaria P (2003) CD40 ligation releases immature dendritic cells from the control of regulatory CD4 + CD25+ T cells. Immunity 19:877–889

    Article  CAS  PubMed  Google Scholar 

  • Stolp J, Chen YG, Cox SL, Henck V, Zhang W, Tsaih SW, Chapman H, Stearns T, Serreze DV, Silveira PA (2012) Subcongenic analyses reveal complex interactions between distal chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in nonobese diabetic mice. J Immunol 189:1406–1417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan IK, Mackin L, Wang N, Papenfuss AT, Elso CM, Ashton MP, Quirk F, Phipson B, Bahlo M, Speed TP, Smyth GK, Morahan G, Brodnicki TC (2010) A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility. Genome Res 20:1629–1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Todd JA (2010) Etiology of type 1 diabetes. Immunity 32:457–467

    Article  CAS  PubMed  Google Scholar 

  • Tritt M, Sgouroudis E, d'Hennezel E, Albanese A, Piccirillo CA (2008) Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes. Diabetes 57:113–123

    Article  CAS  PubMed  Google Scholar 

  • Verdaguer J, Schmidt D, Amrani A, Anderson B, Averill N, Santamaria P (1997) Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J Exp Med 186:1663–1676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waldner H, Sobel RA, Price N, Kuchroo VK (2006) The autoimmune diabetes locus Idd9 regulates development of type 1 diabetes by affecting the homing of islet-specific T cells. J Immunol 176:5455–5462

    Article  CAS  PubMed  Google Scholar 

  • Wicker LS, Clark J, Fraser HI, Garner VE, Gonzalez-Munoz A, Healy B, Howlett S, Hunter K, Rainbow D, Rosa RL, Smink LJ, Todd JA, Peterson LB (2005) Type 1 diabetes genes and pathways shared by humans and NOD mice. J Autoimmun 25(Suppl):29–33

    Article  CAS  PubMed  Google Scholar 

  • Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, Peterson LB, Wicker LS, Santamaria P (2007) Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet 39:329–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamanouchi J, Puertas MC, Verdaguer J, Lyons PA, Rainbow DB, Chamberlain G, Hunter KM, Peterson LB, Wicker LS, Santamaria P (2010) Idd9.1 locus controls the suppressive activity of FoxP3 + CD4 + CD25+ regulatory T-cells. Diabetes 59:272–281

    Article  CAS  PubMed  Google Scholar 

  • Zhao D, Zhang C, Yi T, Lin CL, Todorov I, Kandeel F, Forman S, Zeng D (2008) In vivo-activated CD103 + CD4+ regulatory T cells ameliorate ongoing chronic graft-versus-host disease. Blood 112:2129–2138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Linda Wicker for providing us the Idd9 congenic stock (line 905). This work was supported by the National Institutes of Health grants DK077443, DK097605, AI110963, and AI125879 (to Y.-G. Chen), DK46266 and DK95735 (to D.V.S.), a Basic Science Award (1-10-BS-26) from the American Diabetes Association (to Y.-G. Chen), and the Children’s Hospital of Wisconsin Foundation.

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Author notes

  1. Erin MacKinney

    Present address: Southern Illinois University School of Medicine, Springfield, IL, 62702, USA

Authors and Affiliations

  1. Department of Pediatrics, Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Bixuan Lin, Ashley E. Ciecko, Erin MacKinney & Yi-Guang Chen

  2. The Jackson Laboratory, Bar Harbor, ME, 04609, USA

    David V. Serreze

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  1. Bixuan Lin
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  2. Ashley E. Ciecko
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Correspondence to Yi-Guang Chen.

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Bixuan Lin and Ashley E. Ciecko contributed equally to this work.

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Lin, B., Ciecko, A.E., MacKinney, E. et al. Congenic mapping identifies a novel Idd9 subregion regulating type 1 diabetes in NOD mice. Immunogenetics 69, 193–198 (2017). https://doi.org/10.1007/s00251-016-0957-3

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