Breaking T cell tolerance to beta cell antigens by merocytic dendritic cells

Review

Abstract

In type 1 diabetes (T1D), a break in central and peripheral tolerance results in antigen-specific T cells destroying insulin-producing, pancreatic beta cells. Herein, we discuss the critical sub-population of dendritic cells responsible for mediating both the cross-presentation of islet antigen to CD8+ T cells and the direct presentation of beta cell antigen to CD4+ T cells. These cells, termed merocytic dendritic cells (mcDC), are more numerous in non-obese diabetic (NOD), and antigen-loaded mcDC rescue CD8+ T cells from peripheral anergy and deletion, and stimulate islet-reactive CD4+ T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDC can break peripheral T cell tolerance to beta cell antigens in vivo and induce rapid onset T cell-mediated T1D in young NOD mouse. Thus, the mcDC subset appears to represent the long-sought critical antigen-presenting cell responsible for breaking peripheral tolerance to beta cell antigen in vivo.

Keywords

Type 1 diabetes NOD mice Merocytic dendritic cells Tolerance 

Abbreviations

T1D

Type 1 diabetes

Ag

Antigen(s)

TCR

T cell receptor

APC

Antigen-presenting cell

DC

Dendritic cell(s)

FLT3

Fms-like tyrosine kinase 3

FLT3L

FLT3 ligand

mcDC

Merocytic dendritic cells

IKDC

Natural killer dendritic cells

Th1/Tc1

T helper cell type 1/T cytotoxic cell type 1

pDC

Plasmacytoid dendritic cells

cDC

Conventional dendritic cells

PLN

Pancreatic lymph nodes

CLP

Common lymphoid precursors

CMP

Common myeloid precursors

NOD

Non-obese diabetic

References

  1. 1.
    Atkinson MA (2005) ADA Outstanding Scientific Achievement Lecture 2004. Thirty years of investigating the autoimmune basis for type 1 diabetes: why can’t we prevent or reverse this disease? Diabetes 54:1253–1263PubMedCrossRefGoogle Scholar
  2. 2.
    Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G (2009) Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 373:2027–2033PubMedCrossRefGoogle Scholar
  3. 3.
    Vehik K, Hamman RF, Lezotte D, Norris JM, Klingensmith G, Bloch C, Rewers M, Dabelea D (2007) Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth. Diabetes Care 30:503–509PubMedCrossRefGoogle Scholar
  4. 4.
    Cordell HJ, Todd JA (1995) Multifactorial inheritance in type 1 diabetes. Trends Genet 11:499–504PubMedCrossRefGoogle Scholar
  5. 5.
    Cordell HJ, Todd JA, Lathrop GM (1998) Mapping multiple linked quantitative trait loci in non-obese diabetic mice using a stepwise regression strategy. Genet Res 71:51–64PubMedCrossRefGoogle Scholar
  6. 6.
    Ridgway WM (2003) The non obese diabetic (NOD) mouse: a unique model for understanding the interaction between genetics and T cell responses. Rev Endocr Metab Disord 4:263–269PubMedCrossRefGoogle Scholar
  7. 7.
    Wicker LS, Miller BJ, Mullen Y (1986) Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes 35:855–860PubMedCrossRefGoogle Scholar
  8. 8.
    Bedossa P, Bendelac A, Bach JF, Carnaud C (1989) Syngeneic T cell transfer of diabetes into NOD newborn mice: in situ studies of the autoimmune steps leading to insulin-producing cell destruction. Eur J Immunol 19:1947–1951PubMedCrossRefGoogle Scholar
  9. 9.
    Bendelac A, Carnaud C, Boitard C, Bach JF (1987) Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med 166:823–832PubMedCrossRefGoogle Scholar
  10. 10.
    Katz J, Benoist C, Mathis D (1993) Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur J Immunol 23:3358–3360PubMedCrossRefGoogle Scholar
  11. 11.
    Wicker LS, Leiter EH, Todd JA, Renjilian RJ, Peterson E, Fischer PA, Podolin PL, Zijlstra M, Jaenisch R, Peterson LB (1994) Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 43:500–504PubMedCrossRefGoogle Scholar
  12. 12.
    Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC (1994) Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Diabetes 43:505–509PubMedCrossRefGoogle Scholar
  13. 13.
    Wändell PE (2005) Quality of life of patients with diabetes mellitus: an overview of research in primary health care in the Nordic countries. Scand J Prim Health Care 23:68–74PubMedCrossRefGoogle Scholar
  14. 14.
    Anonoymous (2005) Guidelines. National Institute of Clinical Excellence. Diabet Med 22(Suppl 1):5–6Google Scholar
  15. 15.
    Yagi H, Matsumoto M, Kunimoto K, Kawaguchi J, Makino S, Harada M (1992) Analysis of the roles of CD4+ and CD8+ T cells in autoimmune diabetes of NOD mice using transfer to NOD athymic nude mice. Eur J Immunol 22:2387–2393PubMedCrossRefGoogle Scholar
  16. 16.
    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 42:44–55PubMedCrossRefGoogle Scholar
  17. 17.
    Hayward AR, Shriber M, Cooke A, Waldmann H (1993) Prevention of diabetes but not insulitis in NOD mice injected with antibody to CD4. J Autoimmun 6:301–310PubMedCrossRefGoogle Scholar
  18. 18.
    Wang B, Gonzalez A, Benoist C, Mathis D (1996) The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. Eur J Immunol 26:1762–1769PubMedCrossRefGoogle Scholar
  19. 19.
    Serreze DV, Gallichan WS, Snider DP, Croitoru K, Rosenthal KL, Leiter EH, Christianson GJ, Dudley ME, Roopenian DC (1996) MHC class I-mediated antigen presentation and induction of CD8+ cytotoxic T-cell responses in autoimmune diabetes-prone NOD mice. Diabetes 45:902–908PubMedCrossRefGoogle Scholar
  20. 20.
    Katz JD, Wang B, Haskins K, Benoist C, Mathis D (1993) Following a diabetogenic T cell from genesis through pathogenesis. Cell 74:1089–1100PubMedCrossRefGoogle Scholar
  21. 21.
    Tsai S, Shameli A, Santamaria P (2008) CD8+ T cells in type 1 diabetes. Adv Immunol 100:79–124PubMedCrossRefGoogle Scholar
  22. 22.
    DiLorenzo TP, Serreze DV (2005) The good turned ugly: immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice. Immunol Rev 204:250–263PubMedCrossRefGoogle Scholar
  23. 23.
    Dilts SM, Solvason N, Lafferty KJ (1999) The role of CD4 and CD8 T cells in the development of autoimmune diabetes. J Autoimmun 13:285–290PubMedCrossRefGoogle Scholar
  24. 24.
    Wong FS, Janeway CAJ (1997) The role of CD4 and CD8 T cells in type I diabetes in the NOD mouse. Res Immunol 148:327–332PubMedCrossRefGoogle Scholar
  25. 25.
    Haskins K, Wegmann D (1996) Diabetogenic T-cell clones. Diabetes 45:1299–1305PubMedCrossRefGoogle Scholar
  26. 26.
    André I, Gonzalez A, Wang B, Katz J, Benoist C, Mathis D (1996) Checkpoints in the progression of autoimmune disease: lessons from diabetes models. Proc Natl Acad Sci USA 93:2260–2263PubMedCrossRefGoogle Scholar
  27. 27.
    Kurrer MO, Pakala SV, Hanson HL, Katz JD (1997) Beta cell apoptosis in T cell-mediated autoimmune diabetes. Proc Natl Acad Sci USA 94:213–218PubMedCrossRefGoogle Scholar
  28. 28.
    Pakala SV, Chivetta M, Kelly CB, Katz JD (1999) In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha. J Exp Med 189:1053–1062PubMedCrossRefGoogle Scholar
  29. 29.
    Mathis D, Vence L, Benoist C (2001) Beta-cell death during progression to diabetes. Nature 414:792–798PubMedCrossRefGoogle Scholar
  30. 30.
    O’Brien BA, Harmon BV, Cameron DP, Allan DJ (1997) Apoptosis is the mode of beta-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. Diabetes 46:750–757PubMedCrossRefGoogle Scholar
  31. 31.
    O’Brien BA, Huang Y, Geng X, Dutz JP, Finegood DT (2002) Phagocytosis of apoptotic cells by macrophages from NOD mice is reduced. Diabetes 51:2481–2488PubMedCrossRefGoogle Scholar
  32. 32.
    O’Brien BA, Geng X, Orteu CH, Huang Y, Ghoreishi M, Zhang Y, Bush JA, Li G, Finegood DT, Dutz JP (2006) A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse. J Autoimmun 26:104–115PubMedCrossRefGoogle Scholar
  33. 33.
    Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401PubMedCrossRefGoogle Scholar
  34. 34.
    Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227–239PubMedCrossRefGoogle Scholar
  35. 35.
    Mathis D, Benoist C (2007) A decade of AIRE. Nat Rev Immunol 7:645–650PubMedCrossRefGoogle Scholar
  36. 36.
    Mathis D, Benoist C (2009) Aire. Annu Rev Immunol 27:287–312PubMedCrossRefGoogle Scholar
  37. 37.
    Haskins K, Portas M, Bradley B, Wegmann D, Lafferty K (1988) T-lymphocyte clone specific for pancreatic islet antigen. Diabetes 37:1444–1448PubMedCrossRefGoogle Scholar
  38. 38.
    Bradley BJ, Wang YY, Lafferty KJ, Haskins K (1990) In vivo activity of an islet-reactive T-cell clone. J Autoimmun 3:449–456PubMedCrossRefGoogle Scholar
  39. 39.
    Stadinski BD, Delong T, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, Piganelli JD, Barbour G, Bradley B, Crawford F, Marrack P, Mahata SK, Kappler JW, Haskins K (2010) Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol 11:225–231PubMedCrossRefGoogle Scholar
  40. 40.
    Kanagawa O, Shimizu J, Vaupel BA (2000) Thymic and postthymic regulation of diabetogenic CD8 T cell development in TCR transgenic nonobese diabetic (NOD) mice. J Immunol 164:5466–5473PubMedGoogle Scholar
  41. 41.
    Cain JA, Smith JA, Ondr JK, Wang B, Katz JD (2006) NKT cells and IFN-gamma establish the regulatory environment for the control of diabetogenic T cells in the nonobese diabetic mouse. J Immunol 176:1645–1654PubMedGoogle Scholar
  42. 42.
    Lühder F, Katz J, Benoist C, Mathis D (1998) Major histocompatibility complex class II molecules can protect from diabetes by positively selecting T cells with additional specificities. J Exp Med 187:379–387PubMedCrossRefGoogle Scholar
  43. 43.
    Höglund P, Mintern J, Waltzinger C, Heath W, Benoist C, Mathis D (1999) Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med 189:331–339PubMedCrossRefGoogle Scholar
  44. 44.
    Santamaria P, Utsugi T, Park BJ, Averill N, Kawazu S, Yoon JW (1995) Beta-cell-cytotoxic CD8+ T cells from nonobese diabetic mice use highly homologous T cell receptor alpha-chain CDR3 sequences. J Immunol 154:2494–2503PubMedGoogle Scholar
  45. 45.
    Santamaria P (2010) The long and winding road to understanding and conquering type 1 diabetes. Immunity 32:437–445PubMedCrossRefGoogle Scholar
  46. 46.
    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 USA 95:12538–12543PubMedCrossRefGoogle Scholar
  47. 47.
    Haskins K (2004) T-cell receptor transgenic (TCR-Tg) mice from two diabetogenic CD4+ islet-antigen-specific T-cell clones. J Autoimmun 22:107–109PubMedCrossRefGoogle Scholar
  48. 48.
    Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117:2553–2561PubMedCrossRefGoogle Scholar
  49. 49.
    Brennand K, Huangfu D, Melton D (2007) All beta cells contribute equally to islet growth and maintenance. PLoS Biol 5:e163PubMedCrossRefGoogle Scholar
  50. 50.
    Gu G, Dubauskaite J, Melton DA (2002) Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129:2447–2457PubMedGoogle Scholar
  51. 51.
    Finegood DT, Scaglia L, Bonner-Weir S (1995) Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44:249–256PubMedCrossRefGoogle Scholar
  52. 52.
    Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138:1736–1741PubMedCrossRefGoogle Scholar
  53. 53.
    Petrik J, Arany E, McDonald TJ, Hill DJ (1998) Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor. Endocrinology 139:2994–3004PubMedCrossRefGoogle Scholar
  54. 54.
    Turley S, Poirot L, Hattori M, Benoist C, Mathis D (2003) Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med 198:1527–1537PubMedCrossRefGoogle Scholar
  55. 55.
    Belz GT, Carbone FR, Heath WR (2002) Cross-presentation of antigens by dendritic cells. Crit Rev Immunol 22:439–448PubMedGoogle Scholar
  56. 56.
    Belz GT, Shortman K, Bevan MJ, Heath WR (2005) CD8alpha+ dendritic cells selectively present MHC class I-restricted noncytolytic viral and intracellular bacterial antigens in vivo. J Immunol 175:196–200PubMedGoogle Scholar
  57. 57.
    Roos A, Xu W, Castellano G, Nauta AJ, Garred P, Daha MR, van Kooten C (2004) Mini-review: a pivotal role for innate immunity in the clearance of apoptotic cells. Eur J Immunol 34:921–929PubMedCrossRefGoogle Scholar
  58. 58.
    Janssen E, Tabeta K, Barnes MJ, Rutschmann S, McBride S, Bahjat KS, Schoenberger SP, Theofilopoulos AN, Beutler B, Hoebe K (2006) Efficient T cell activation via a Toll-interleukin 1 receptor-independent pathway. Immunity 24:787–799PubMedCrossRefGoogle Scholar
  59. 59.
    Liu K, Nussenzweig MC (2010) Origin and development of dendritic cells. Immunol Rev 234:45–54PubMedCrossRefGoogle Scholar
  60. 60.
    Schmid MA, Kingston D, Boddupalli S, Manz MG (2010) Instructive cytokine signals in dendritic cell lineage commitment. Immunol Rev 234:32–44PubMedCrossRefGoogle Scholar
  61. 61.
    Steinman RM, Idoyaga J (2010) Features of the dendritic cell lineage. Immunol Rev 234:5–17PubMedCrossRefGoogle Scholar
  62. 62.
    Bedoui S, Prato S, Mintern J, Gebhardt T, Zhan Y, Lew AM, Heath WR, Villadangos JA, Segura E (2009) Characterization of an immediate splenic precursor of CD8+ dendritic cells capable of inducing antiviral T cell responses. J Immunol 182:4200–4207PubMedCrossRefGoogle Scholar
  63. 63.
    Qiu C, Miyake Y, Kaise H, Kitamura H, Ohara O, Tanaka M (2009) Novel subset of CD8{alpha}+ dendritic cells localized in the marginal zone is responsible for tolerance to cell-associated antigens. J Immunol 182:4127–4136PubMedCrossRefGoogle Scholar
  64. 64.
    Bonmort M, Dalod M, Mignot G, Ullrich E, Chaput N, Zitvogel L (2008) Killer dendritic cells: IKDC and the others. Curr Opin Immunol 20:558–565PubMedCrossRefGoogle Scholar
  65. 65.
    Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258PubMedCrossRefGoogle Scholar
  66. 66.
    Allan RS, Waithman J, Bedoui S, Jones CM, Villadangos JA, Zhan Y, Lew AM, Shortman K, Heath WR, Carbone FR (2006) Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25:153–162PubMedCrossRefGoogle Scholar
  67. 67.
    Savina A, Amigorena S (2007) Phagocytosis and antigen presentation in dendritic cells. Immunol Rev 219:143–156PubMedCrossRefGoogle Scholar
  68. 68.
    Williams CA, Harry RA, McLeod JD (2008) Apoptotic cells induce dendritic cell-mediated suppression via interferon-gamma-induced IDO. Immunology 124:89–101PubMedCrossRefGoogle Scholar
  69. 69.
    Peng YF, Elkon KB (2007) Peripheral CD8 T-cell responses to apoptotic cell proteins and peptides. Crit Rev Immunol 27:357–365PubMedGoogle Scholar
  70. 70.
    Ferguson TA, Kazama H (2005) Signals from dying cells: tolerance induction by the dendritic cell. Immunol Res 32:99–108PubMedCrossRefGoogle Scholar
  71. 71.
    Saas P, Bonnefoy F, Kury-Paulin S, Kleinclauss F, Perruche S (2007) Mediators involved in the immunomodulatory effects of apoptotic cells. Transplantation 84:S31–S34PubMedCrossRefGoogle Scholar
  72. 72.
    Shortman K, Heath WR (2010) The CD8+ dendritic cell subset. Immunol Rev 234:18–31PubMedCrossRefGoogle Scholar
  73. 73.
    Schulz O, Reis e Sousa C (2002) Cross-presentation of cell-associated antigens by CD8alpha+ dendritic cells is attributable to their ability to internalize dead cells. Immunology 107:183–189PubMedCrossRefGoogle Scholar
  74. 74.
    Iyoda T, Shimoyama S, Liu K, Omatsu Y, Akiyama Y, Maeda Y, Takahara K, Steinman RM, Inaba K (2002) The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 195:1289–1302PubMedCrossRefGoogle Scholar
  75. 75.
    Crozat K, Guiton R, Contreras V, Feuillet V, Dutertre C, Ventre E, Vu Manh T, Baranek T, Storset AK, Marvel J, Boudinot P, Hosmalin A, Schwartz-Cornil I, Dalod M (2010) The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. J Exp Med 207:1283–1292PubMedCrossRefGoogle Scholar
  76. 76.
    Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, Chen CJ, Dunbar PR, Wadley RB, Jeet V, Vulink AJE, Hart DNJ, Radford KJ (2010) Human CD141+(BDCA-3) + dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med 207:1247–1260PubMedCrossRefGoogle Scholar
  77. 77.
    Bachem A, Güttler S, Hartung E, Ebstein F, Schaefer M, Tannert A, Salama A, Movassaghi K, Opitz C, Mages HW, Henn V, Kloetzel P, Gurka S, Kroczek RA (2010) Superior antigen cross-presentation and XCR1 expression define human CD11c+ CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp Med 207:1273–1281PubMedCrossRefGoogle Scholar
  78. 78.
    Hoeffel G, Ripoche A, Matheoud D, Nascimbeni M, Escriou N, Lebon P, Heshmati F, Guillet J, Gannagé M, Caillat-Zucman S, Casartelli N, Schwartz O, De la Salle H, Hanau D, Hosmalin A, Marañón C (2007) Antigen crosspresentation by human plasmacytoid dendritic cells. Immunity 27:481–492PubMedCrossRefGoogle Scholar
  79. 79.
    Colonna M, Cella M (2007) Crosspresentation: plasmacytoid dendritic cells are in the business. Immunity 27:419–421PubMedCrossRefGoogle Scholar
  80. 80.
    Irla M, Küpfer N, Suter T, Lissilaa R, Benkhoucha M, Skupsky J, Lalive PH, Fontana A, Reith W, Hugues S (2010) MHC class II-restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell-mediated autoimmunity. J Exp Med 207:1891–1905PubMedCrossRefGoogle Scholar
  81. 81.
    Hennies CM, Reboulet RA, Garcia Z, Nierkens S, Wolkers MC, Janssen EM (2011) Selective expansion of merocytic dendritic cells and CD8DCs confers anti-tumour effect of Fms-like tyrosine kinase 3-ligand treatment in vivo. Clin Exp Immunol 163:381–391PubMedCrossRefGoogle Scholar
  82. 82.
    Reboulet RA, Hennies CM, Garcia Z, Nierkens S, Janssen EM (2010) Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice. J Immunol 185:3337–3347PubMedCrossRefGoogle Scholar
  83. 83.
    Steptoe RJ, Ritchie JM, Harrison LC (2003) Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes. J Clin Invest 111:1357–1363PubMedGoogle Scholar
  84. 84.
    Spierings DCJ, Lemmens EE, Grewal K, Schoenberger SP, Green DR (2006) Duration of CTL activation regulates IL-2 production required for autonomous clonal expansion. Eur J Immunol 36:1707–1717PubMedCrossRefGoogle Scholar
  85. 85.
    Kaech SM, Ahmed R (2001) Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells. Nat Immunol 2:415–422PubMedGoogle Scholar
  86. 86.
    Belz GT, Kallies A (2010) Effector and memory CD8+ T cell differentiation: toward a molecular understanding of fate determination. Curr Opin Immunol 22:279–285PubMedCrossRefGoogle Scholar
  87. 87.
    Marrack P, Kappler J, Mitchell T (1999) Type I interferons keep activated T cells alive. J Exp Med 189:521–530PubMedCrossRefGoogle Scholar
  88. 88.
    Le Bon A, Durand V, Kamphuis E, Thompson C, Bulfone-Paus S, Rossmann C, Kalinke U, Tough DF (2006) Direct stimulation of T cells by type I IFN enhances the CD8 + T cell response during cross-priming. J Immunol 176:4682–4689PubMedGoogle Scholar
  89. 89.
    Huber JP, David Farrar J (2011) Regulation of effector and memory T-cell functions by type I interferon. Immunology 132:466–474PubMedCrossRefGoogle Scholar
  90. 90.
    Sun JC, Bevan MJ (2003) Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300:339–342PubMedCrossRefGoogle Scholar
  91. 91.
    Shedlock DJ, Shen H (2003) Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300:337–339PubMedCrossRefGoogle Scholar
  92. 92.
    Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP (2003) CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421:852–856PubMedCrossRefGoogle Scholar
  93. 93.
    Hamilton-Williams EE, Lang A, Benke D, Davey GM, Wiesmüller K, Kurts C (2005) Cutting edge: TLR ligands are not sufficient to break cross-tolerance to self-antigens. J Immunol 174:1159–1163PubMedGoogle Scholar
  94. 94.
    Krawczyk CM, Shen H, Pearce EJ (2007) Memory CD4 T cells enhance primary CD8 T-cell responses. Infect Immun 75:3556–3560PubMedCrossRefGoogle Scholar
  95. 95.
    Williams MA, Holmes BJ, Sun JC, Bevan MJ (2006) Developing and maintaining protective CD8+ memory T cells. Immunol Rev 211:146–153PubMedCrossRefGoogle Scholar
  96. 96.
    Rosmalen JG, Leenen PJ, Katz JD, Voerman JS, Drexhage HA (1997) Dendritic cells in the autoimmune insulitis in NOD mouse models of diabetes. Adv Exp Med Biol 417:291–294PubMedGoogle Scholar
  97. 97.
    Jansen A, Homo-Delarche F, Hooijkaas H, Leenen PJ, Dardenne M, Drexhage HA (1994) Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and beta-cell destruction in NOD mice. Diabetes 43:667–675PubMedCrossRefGoogle Scholar
  98. 98.
    de Jong MAWP, Geijtenbeek TBH (2010) Langerhans cells in innate defense against pathogens. Trends Immunol 31:452–459PubMedCrossRefGoogle Scholar
  99. 99.
    Nikolic T, Bouma G, Drexhage HA, Leenen PJM (2005) Diabetes-prone NOD mice show an expanded subpopulation of mature circulating monocytes, which preferentially develop into macrophage-like cells in vitro. J Leukoc Biol 78:70–79PubMedCrossRefGoogle Scholar
  100. 100.
    Nikolic T, Geutskens SB, van Rooijen N, Drexhage HA, Leenen PJ M (2005) Dendritic cells and macrophages are essential for the retention of lymphocytes in (peri)-insulitis of the nonobese diabetic mouse: a phagocyte depletion study. Lab Invest 85:487–501PubMedCrossRefGoogle Scholar
  101. 101.
    Saxena V, Ondr JK, Magnusen AF, Munn DH, Katz JD (2007) The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J Immunol 179:5041–5053PubMedGoogle Scholar
  102. 102.
    Katz JD, Ondr JK, Opoka RJ, Garcia Z, Janssen EM (2010) Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. J Immunol 185:1999–2003PubMedCrossRefGoogle Scholar
  103. 103.
    Li Q, Xu B, Michie SA, Rubins KH, Schreriber RD, McDevitt HO (2008) Interferon-alpha initiates type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci USA 105:12439–12444PubMedCrossRefGoogle Scholar

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© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Division of Endocrinology, Department of Pediatrics, Cincinnati Children’s Research FoundationUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Division of Molecular Immunology, Department of Pediatrics, Cincinnati Children’s Research FoundationUniversity of Cincinnati College of MedicineCincinnatiUSA

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