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Pancreatic lymph node. Islet. CD8 +. En- viron- ment. Perforin?. Co-stimu- latory signals. •. •. •. •. DC. •. •. •. •. •. •. •. •. •. •. •. •. . •. •. •. •. DC. •. •. •. •. IL-1 TNF . O 2. NO. •. •. . •. Th 1. •. •. •. •. •. •. •.

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O 2

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  1. Pancreatic lymph node Islet CD8+ En-viron-ment Perforin? Co-stimu- latory signals • • • • DC • • • • • • • • • • • •  • • • • DC • • • • IL-1 TNF O2 NO • •  • Th1 • • • • • • • • • MØ • • Fas FasL IFN T- and B-cell clonal ex- pansion Th1 Mandrup-Poulson

  2. SOD2 NOS2 NFKB BCL2 INS T1DM FASL FAS CTLA4 CD4 IL6 IL12B IL1RN IL1RI IFNG HLA TNFA IL1B Mandrup-Poulson

  3. IFNg IL-1ß Cytokine-signaling  Energy generation  Defense  Repair  NO production Mitochondria  Apoptosis  Insulin production/ß-cell function ß-cell destruction Mandrup-Poulson

  4. Mandrup-Poulson

  5. Mitogen and stress stimuli Ras Rho TRAF MAPKKK Raf ASK MEKK MLK TAK1 TPL2 ATP ADP MEK1/2 MKK3/6 MKK4/7 MAPKK ATP ADP ERK p38 JNK MAPK Elk-1 ATF2 c-jun Mandrup-Poulson

  6. TNF IL-1 TNF IL-1 p60 IL-1R1 IL-1AcP MyD88 TRADD TRAF2 IRAK TRAF6 FADD NIK IKK IkB NFkB IkB NFkB Gene expression Cellular response Mandrup-Poulson

  7. IFN IFN IFN IFNgR1 IFNgR2 IFNgR2 P STAT1 JAK1 JAK1 JAK1 JAK1 JAK1 JAK2 JAK2 STAT1 P STAT1 Translocation to nucleus Gene expression Mandrup-Poulson

  8.  energy generation  insulin production/ß-cell function  defense  NO production +cytokines  cytokine-signaling  apoptosis  repair ß-cell survival ß-cell destruction Mandrup-Poulson

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