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Signaling in the immune system André Veillette University of Toronto November 29, 2006

Signaling in the immune system André Veillette University of Toronto November 29, 2006. Figure 1-3. The immune system is constituted by multiple cell types with different functions. Two types of immunity :

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Signaling in the immune system André Veillette University of Toronto November 29, 2006

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  1. Signaling in the immune system André Veillette University of Toronto November 29, 2006

  2. Figure 1-3 The immune system is constituted by multiple cell types with different functions

  3. Two types of immunity: 1) Innate immunity (macrophages, dendritic cells, natural killer cells) – more primitive 2) Adaptive immunity (T cells, B cells) – more evolved; allows antigen specificity

  4. Innate immunity

  5. Figure 1-4 part 1 of 3

  6. Figure 1-4 part 2 of 3

  7. Figure 1-4 part 3 of 3

  8. Figure 1-6

  9. Adaptive immunity

  10. Figure 1-14 part 2 of 2

  11. Figure 1-19 B cells produce antibodies against specific antigens T cells produce cytokines or can kill in response to specific antigens

  12. The two types of immunity are mediated by different classes of receptors, using distinct signaling mechanims

  13. Figure 2-10

  14. Signaling mechanisms used by immune cells: • Immunoreceptors • Cytokine receptors • Toll-like receptors (TLRs) • 4) SLAM family receptors.

  15. Immunoreceptors • central to the activation of all immune cells • function by activating protein tyrosine • phosphorylation

  16. ITAM: « immunoreceptor tyrosine-based activation motif » • YxxL/I-6-7-YxxL/I • ITAMs trigger protein tyrosine phosphorylation by enabling the • sequential recruitment of two classes of cytoplasmic protein • tyrosine kinases

  17. K273 Y505 Y394 C N SH3 SH2 kinase Y317 K396 Y519/520 N C kinase SH2 SH2 Protein tyrosine kinases in immunoreceptor signaling Lck Zap-70/ Syk

  18. N unique linker Csk-PEP SH3 CD45 kinase SH2 P C Regulation of Src family protein tyrosine kinases N unique SH3 SH2 linker P Y394 kinase Y505 C inactive Src kinase (Lck) activated Src kinase (Lck)

  19. Figure 6-12

  20. Figure 6-16 part 2 of 2

  21. Figure 6-8

  22. Figure 6-14

  23. Figure 6-19

  24. ITAM: « immunoreceptor tyrosine-based activation motif » • YxxL/I-6-7-YxxL/I • ITAMs trigger protein tyrosine phosphorylation by enabling the • sequential recruitment of two classes of cytoplasmic protein • tyrosine kinases

  25. Figure 8-31

  26. Figure 8-32

  27. Cytokine receptors • amplify immune responses • function by inducing protein tyrosine • phosphorylation

  28. Figure 8-33

  29. Figure 6-23 part 1 of 2

  30. Figure 6-23 part 2 of 2

  31. Toll-like receptors (TLRs) • expressed on innate immune cells • such as DCs and macrophages • are triggered by pathogen-associated • molecular patterns (PAMPs) • function by activating NFkB

  32. Figure 2-12

  33. Figure 6-21 part 1 of 2

  34. Figure 6-21 part 2 of 2

  35. Conclusions (Part I): 1) Multiple cell types are involved in immunity 2) Two types of immunity exist: innate and adaptive 3) Immune cells utilize several types of specialized receptors to control cellular functions, including immunoreceptors, cytokine receptors and Toll-like receptors 4) These receptors mediate their signals through unique and interesting mechanisms.

  36. SLAM family receptors

  37. Y Y Y Y Y Y Y Y Y Y SLAM-related receptors NTB-A (Ly108) Ly-9 CRACC CD48 CD84 SLAM measles Ligands Ly-9 V NTB-A (Ly108) 2B4 CRACC SLAM CD84 C2 V V V V V V C2 C2 C2 C2 C2 C2 Y Y Y Y : TIYxxV/Imotif Y Y Y Y Y Y Y : TVYxxV/Imotif Y Y Y Y Y Y

  38. Expression pattern Chromosome SAP (SH2D1A) SH2 T, NK, NK-T, eo,?B,plat X 47% 0% EAT-2 (SH2D1B) SH2 NK, DC, MF, ?plat 1 Y Y 85% 73% ERT (SH2D1C) SH2 Y Y NK (mouse) 1 SLAM-related receptors associate with SAP family adaptors

  39. Roles of SAP (and, presumably, SLAM-related receptors) in immunity • The SAP gene is mutated in 50-70% of cases of X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by an abnormal response to EBV infection with fatal infectious mononucleosis, as well as a high frequency of hypogammaglobulinemias and malignant lymphomas; • SAP-deficient mice exhibit abnormal CD4+ T cell help (decreased TH2 functions), decreased Ig production, defective memory B cells, reduced NK cell cytotoxicity, absent NKT cells and altered anti-viral responses.

  40. SAP is required for SLAM-induced protein tyrosine phosphorylation

  41. SAP is a bifunctional adaptor linking SLAM-related receptors to FynT, a Src family kinase

  42. The FynT SH3 domain binds an arginine-based motif at the surface of the SAP SH2 domain SH2 domain 1 30 SAP(m)MDAVTVYHGKISRETGEKLLLATGLDGSYLLRDSESVPGVYCLCVLYQGYIYTYRVSQTETGSWSAE SAP(h)MDAVAVYHGKISRETGEKLLLATGLDGSYLLRDSESVPGVYCLCVLYHGYIYTYRVSQTETGSWSAE EAT-2(m)MD.LPYYHGCLTKRECEALLLKGGVDGNFLIRDSESVPGALCLCVSFKKLVYSYRIFREKHGYYRIE EAT-2(h)MD.LPYYHGRLTKQDCETLLLKEGVDGNFLLRDSESIPGVLCLCVSFKNIVYTYRIFREKHGYYRIQ 68 126 SAP(m)TAPGVHKRFFRKVKNLISAFQKPDQGIVTPLQYPVE.KSSGRGPQAPTG.RRDSDICLNAP SAP(h)TAPGVHKRYFRKIKNLISAFQKPDQGIVIPLQYPVEKKSSARSTQGTTGIREDPDVCLKAP EAT-2(m)TDAHTPRTIFPNLQELVSKYGKPGQGLVVHLSNPIMRNNLC...QRGRRMELELNVYENTDEEYVDVLP EAT-2(h)TAEGSPKQVFPSLKELISKFEKPNQGMVVHLLKPIKRTSPS...LRWRGLKLELETFVNSNSDYVDVLP A 1 B C D E tail * * * * * * * F 2 G

  43. Crystal structure SAP SH2-FynT SH3 complex Chan et al., 2003

  44. Creation of a sapR78A“knock-in” mouse floxed sapR78A allele * * cgggcg TGA ATG sapR78A loxP exon 1 exon 2 exon 3 exon 4 R78A SH2 domain

  45. Defective SLAM signalling in T cells from sapR78A mice

  46. IL-4 400 350 300 250 IL-4 (pg.ml-1) sap+ 200 sap- sapR78A 150 100 50 0 Anti-CD3: Anti-CD28: 0.3 1 3.0 0 0.3 0 3.0 1 P+I 0 0 TH2 defect in CD4+ T cells from sapR78A mice

  47. fyn-/- T cells exhibit TH2 and, to a lesser extent, TH1 cytokine defects in response to TCR stimulation

  48. DC ? MHC TCR ? T-cell SAP FynT FynT IL-4 IL-13 Regulation of TH2 cytokine production by SAP-FynT pathway Which SLAM family receptors are involved?

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