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Signaling through C-type lectin receptors: shaping immune response

Teunis B. H. Geijtenbeek and Sonja I. Gringhuis Nature Reviews: Immunology, Vol. 9, July 2009, p.465-479 report by: Yuri Yakushko. Signaling through C-type lectin receptors: shaping immune response. Talk overview. Dendritic cells Pathogen recognition C-type lectins classification

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Signaling through C-type lectin receptors: shaping immune response

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  1. Teunis B. H. Geijtenbeek and Sonja I. Gringhuis Nature Reviews: Immunology, Vol. 9, July 2009, p.465-479 report by: Yuri Yakushko Signaling through C-type lectin receptors: shaping immune response

  2. Talk overview Dendritic cells Pathogen recognition C-type lectins classification CLR signaling in general CLRs that interact with TLRs (DC-SIGN) CLRs that interact with TLRs (BDCA2) CLRs that interact with TLRs (DCIR, MICL) TLR-independent signaling by CLRs (dectin 1) TLR-independent signaling by CLRs (dectin 2 and mincle) CLRs and T-cells differentiation Therapeutic potential Future directions. Sum up

  3. DCs: • located throughout the body • capture and process antigens • present antigens with: • MHC I for CD8+ cells • MHC II for CD4+ cells Picture source: www.healthsystem.virginia.edu

  4. Dendritic cells Section of skin showing large numbers of dendritic (Langerhans) cells in the epidermis. CD1a staining www.dermatologyoutlines.com/dermcdmarkers.html

  5. CD4+ cell Regulatory T cell Dendritic cells IFNγ that activates macrophages to fight intracellular infections • Suppress effector T-cells • Some subpopulations of • T-suppressors: • CD8+ cells • CD4, CD25 and Foxp3 • (CD4+CD25+ regulatory T cells • are exclusively called "Tregs") IL-4, IL-5, IL-13 to induce humoral immune response (e.g. against helminths) IL-17 to mobilize phagocytes to clear extracellular fungi and bacteria

  6. Pathogen recognition PAMP – pathogen-associated molecular patterns: groups of pathogens that share similar structures PRR – PAMP Recognition Receptors: • 1. Toll-like receptors (TLRs): • 1,2,4,5,6,10,11 on cell surface • 3,7,8,9 in cell compartments • 2. non-TLRs: • retinoic acid-inducible gene I (RIG-I) • C-type lectin receptors (CLRs)

  7. C-type lectins Lectins are sugar-binding proteins which are highly specific for their sugar moieties Ca2+-independent lectins Ca2+-dependent lectins C-type lectin receptors (CLRs) bind particular sugars in Ca-dependent manner C-type lectin-like molecules bind either carbohydrates, polypeptide ligands or both. • have at least one carbohydrate-recognition domain • can be cytoplasmic or transmembrane • some of them function as PRR (pathogen-associated molecular patterns (PAMP) recognition receptors)

  8. C-type lectin receptors CLRs • Both families of receptors can recognize mannose, fucose, glucans etc. • mannose allows recognition of viruses, fungi and mycobacteria • fucose structures are usually expressed by bacteria and helminths • glucans are present on mycobacteria and fungi mannose-receptor family (e.g. DEC 205) asialoglycoprotein-receptor family (e.g. DC-SIGN, dectin 1) Ag internalization, processing and presentation (on DC) • Some CLRs are expressed be several subsets of DCs: • DC-SIGN and dectin 1 on subepithelial and some myeloid DCs • Other CLRs are specific for particular DC subsets: • langerin (=CLEC4K=CD207) on Langerhans cells (e.g. epedermis), • BDCA2(=CLEC4C) on plasmacytoid DCs

  9. C-type lectin receptors, pathogen recognition and signaling

  10. C-type lectin receptors, pathogen recognition and signaling

  11. Ag-processing via CLRs on dendritic cells 1 1 2 1 2 2 1 3 • CLRs are targeted in vaccine studies to increase Ag-specific immune responses: DEC205 was one of the first targets in these studies • CLEC9A is expressed on mouse CD8+ cells and recognized necrotic cells. When bound to ligand, activates SYK (spleen tyrosine kinase) • for cross-presentation of necrotic cell-associated Ag 1 2 3 Cross-presentation means presenting Ag with MHC I to CD8+ cells

  12. CLRssignaling CLRs signaling through ITAM/ITIM-containing adaptor molecules (e.g.Fc-receptor γ-chain (FcRγ) and DAP12) Protein kinases or phosphatases that direclty or indirectly interact with their cytoplasmic domains • mincle • dectin 2 • BDCA2 • dectin 1 • DC-SIGN • DCIR • MICL ITAM – immunoreceptor tyrosin-based activation motif ITIM – immunoreceptor tyrosin-based inhibition motif

  13. CLRssignaling CLRs ITAM / ITIM-containing adaptor molecules or pKs/phosphatases ?? NF-kB (nuclear transcription factor) inducible gene expression in the immune system

  14. CLRs signaling and TLRs pathways BDCA2, DC-SIGN, DCIR, MICL can modulate TLR-induced gene expression (but only when they are activated by their specific PRR). All these molecules do not effect gene expression without signals, induced by other PRRs. Dectin 1, dectin 2, mincle do not interact with TLRs signaling. But they can induce gene expression without other PRRs.

  15. 1 2 3 4 Nf-kB 5 CLRs that interacts with TLRs pathways Mannose-containing pathogens (e.g. M. tuberculosis, HIV-1, C. albicans, measles virus) 1 DC-SIGN activation TLR4 2 TLR3 TLR5 Ras (GTPase) + RAF1 (Ser/Thr kinase) 3 RAF1-GTP ? Src and PAKs kinases 4 NF-kB RAF1-P ? 5 Dendritic cells-sprecific ICAM3-grabbing non-integrin (DC-SIGN) signaling

  16. 1 ? RAF1-P 2 4 3 CREB (cAMP response element binding) DNA regions called CRE (cAMP response elements) 1 Histone acetyltransferase: increases DNA binding activity of NF-kB p65 subunit NF-kB: subunit p65+P 2 CBP (CREB-binding protein) 3 + CBP + CREB + NF-kB + DNA complex 4 Transcriptional activation of il8 and il10 promoters • IL8 • IL10 Dendritic cells-sprecific ICAM3-grabbing non-integrin (DC-SIGN) signaling

  17. DC-SIGN signaling. Sum up DC-SIGN ? Ras + RAF1 MEK-MAPK/ERK cascade RAF1-MEK-MAPK/ERK-cascade not launched by DC-SIGN (but by anti-DC-SIGN antibody) Nf-kB + CREB-CBP + DNA RAF1-MEK-MAPK/ERK-cascadelaunched by some DC-SIGN ligands (peanut allergen Ara h1 or Schistosoma mansoni egg Ag) il8, il10 genes expression • gp120 of HIV-1 is linked to ERK activation, • but DC-SIGN role not proved • Ixodes scapularis protein (“Salp15”): • activates RAF1, but downstream cascade • does not involve p65 (of Nf-kB). • MEK is activated, but not the following ERK.

  18. 1 1 Ixodes scapularis 3 2 2 Borrelia burgdorferi DC-SIGN signaling plasticity Ras – RAF1 - MEK 1 ? mRNA decay mRNA 3 il6 and Tnf genes 2 TLR 1 So DC-SIGN signaling is of high plasticity and poorly understood. So guys, work more:) I.scapularis spreads B.burgdorferi that causes Lyme disease (borreliosis)

  19. MAPK pathways http://www.genome.jp/kegg/pathway/hsa/hsa04010.html or http://www.kegg.jp

  20. TLR pathway BDCA2 signaling through ITAM-containing FcRγ BDCA2 Fc-receptor γ-chain, bound with ITAM + 1 + 2P 2 1 FcRγ-ITAM-PP SYK (spleen tyrosine kinase) 3 2 BTK (Bruton’s tyrosine kinase) complex BLNK (B-cell linker) PLCγ2 phospholipase 3 ? 4 Ca2+ 4 BDCA2 – Blood DC antigen 2 protein ITAM – immunoreceptor tyrosin-based activation motif

  21. BDCA2 signaling through ITAM-containing FcRγ • Tonic Ca2+ signaling also inhibits TLR pathway via activating calcineurin (phosphatase). Calcineurin then inhibits MYD88 (myeloid differentiation primary response protein 88). • Thus BDCA2, perhaps, also inhibits MYD88 (and downstream TLR-induced pathway) through calcineurin. • In macrophages Ca2+ signaling is induced by TREM2 (triggering-receptor expressed on myeloid cells 2), that also binds to ITAM-proteins and down-regulates TLR-signaling.

  22. CLR signaling through ITIMs DCIR and MICL are the only known CLRs that contain ITIM in their cytoplasmic tails Both molecules are not shown to induce immune responses on their own, but can modulate signaling pathways induced by other PRRs ITIM – immunoreceptor tyrosin-based inhibitory motif

  23. TLR8-mediated IL-12 and TNF production by myeloid DCs TLR9-induced IFNα and TNF production by plasmacytiod DCs DCIR signaling DCIR (with ITIM tail) 1 SH2-domain containing protein tyrosin phosphatases SHP1 or SHP2 1 2 3 ? 2 3 3 3 DCIR – DC immunoreceptor

  24. TLR-induced IL-12 expression MICL signaling MICL (with ITIM tail) 1 SH2-domain containing protein tyrosin phosphatases SHP1 or SHP2 1 2 2 ERK? ? 3 MICL – myeloid C-type lectin like receptor ERK – extracellular signal-regulated kinase

  25. ITIM-bearing molecules sum up • ITIM-bearing molecules seem to suppress cytokine responses induced by other PRR through the recruitment of SHPs. • SHPs decrease the production of TLR-induced pro- inflammatory cytokines • but SHPs increase production of type 1 IFNs induced by TLRs DCIR and MICL pathways plasticity and interaction with TLR signaling are not clear. Well, you already know, right? WORK MORE SHP – SH2-domain containing protein tyrosin phosphatases DCIR – DC immunoreceptor MICL – myeloid C-type lectin like receptor ITIM – immunoreceptor tyrosin-based inhibitory motif

  26. TLR-independent signaling by CLRs. Dectin 1 Dectin 1 induces gene expression independently of other PRRs. Works through recognition of β-1,3-glucan PAMPs that are expressed by many pathogens (C.albicans, Aspergillus fumigatus, Pneumocystis carinii) Dectin 1 – DC-associated C-type lectin 1

  27. TLR-independent signaling by CLRs 2 x Dectin 1 (YxxL motifs, where x – any aa) 1 1 SYK (spleen tyrosine kinase) 2 CARD9 complex 2 BCL-10 MALT1 3 ?? TRAF2-TRAF6 (TNF receptor-associated factors) ? 3 NF-kB (p65 and REL subunits) “canonical NF-kB pathway” 4 4 Dectin 1

  28. Non-canonic NF-kB pathway 2 x Dectin 1 (YxxL motifs, where x – any aa) 1 SYK (spleen tyrosine kinase) 1 NIK (NF-kB-inducing kinase) 2 2 3 IKKα (IkB kinase-α) Never shown to SYK before. Fast kinetics comparing with other inductors suggests that dectin 1 launches unique pathway NF-kB ? 3 NF-kB Dectin 1

  29. Dectin 1. Some more • SYK-CARD9-dependent pathway activated in response to C.albicans leads to activation of NLR family, pyrin domain containing 3 (NLRP3=NALP3) inflammasome. The pathway leads to processing pro-IL-1β to active form IL-1β by caspase 1 through the generation of reactive oxygen species. However, details are unclear and need clarification • SYK also converge with RAF1 pathway, as SYK induces phosphorylation of p65 subunit of NF-kB by RAF1, which, finally, results in induction of il6, il10, il12a and il12b genes transcription. • SYK- and RAF1-pathways fine-tune NF-kB-induced cytokine responses: • p65-P subunits form dimers that cannot bind to DNA. This leads to reduced production of IL-1β, IL-12 and IL-23 – major cytokines for Th differentiation. • Dectin 1 also induces CCL17 and CCL22 production (CC-chemokine ligand) which are involved in the recruitment of other leukocytes. Dectin 1 in the only CLR known to induce non-canonic NF-kB pathway!

  30. Dectin 2 and mincle Both molecules signal through ITAM-containing FcRγ (like BDCA2) Dectin 2 / mincle 1 1 SYK (spleen tyrosine kinase) 2 CARD9-BCL10-MALT1 complex? ? 2 NF-kB • CARD9 – caspase recruitment • domain family, member 9 • BCL10 – B-cell lymphoma 10 • MALT1 – Mucosa associated lymphoid • tissue lymphoma translocation gene 1 ITAM – immunoreceptor tyrosin-based activation motif

  31. Dectin 2 and mincle • C.albicans, Trichophyton rubrum, • Microsporum audouinii • house dust mite allergens Dectin 2 + Pro-inflam. cytokines: TNF, IL-10 CXCL2 neutrophils migrations + dead cells Mincle in macrophages + pathogenic fungus Malassezia spp. CXCL2 TNF

  32. CLRs and T cell differentiation. C.albicans 1 DC-SIGN + Dectin 1 1 + β-glucan structures on C.albicans 2 1 NF-kB 2 differentiation 3 Th1 + Th17 3

  33. CLRs and T cell differentiation. M.tuberculosis 1 DC-SIGN + Dectin 1 1 + mannose on M.tuberculosis 2 NF-kB 2 differentiation 3 Th1 + Th2 + Th17 M.tuberculosis activation mechanisms are not fully understood 3

  34. Therapeutic potential of CLRs signaling CLEC5A inhibition during dengue virus prevents virus-induced plasma leakage and reduces mortality in mice. Patients with SLE have reduced number of pDCs expressing BDCA2 that results in excessive production of type I IFNs, which is major pathophysiological factor in SLE. DCIR deficiency in mice leads to the development of autoimmune diseases, such as rheumatoid arthritis. Dectin 2 triggering by dust mite (Milben) allergens leads to cysteinyl leukotriene production that causes inflammation. Peanut allergen Ara h1 interacts with DC-SIGN and induces Th2-cells responses. • CLR agonists might activate pathways to prevent autoimmune disorders • CLR antagonists could attenuate or modulate inflammation

  35. Vaccination strategies Specific delivery of antigens to DCs (e.g. on Ag-covered particles). This approach was proved to work, but remains expensive and difficult. Targeting DEC205, DC-SIGN or mannose receptor by antibodies induces CD4+ and CD8+ cells responses. This can be used to induce tolerance to pancreatic β-cells, thereby preventing type I diabetes (autoimmune type mediated by T-cell destruction of β-cells). Therapy against β-cell antigens expressed on DEC205 DCs reduces autoreactive CD8+ cells. Mice immunization with zymosan or curdlan (dectin 1 ligands) induces specific CD4+ Th1 and Th17, as well as CD8+ responses through SYK-CRAD9 pathway. So could be used as adjuvants. RAF1 inhibition is also studied, but RAF1 is involved in too many vital mechanisms to be a proper immunomodulatory target. Carbohydrate-expressing ligands lack specificity as are recognized by several CLRs.

  36. Vaccination strategies DC-SIGN + Dectin 1 1 1 + carbohydrate-coated particle with antigens NF-kB 2 2 differentiation 3 Th1 + Th2 + Th17 4 3 Selective inhibition of RAF1 and/or SYK allows the modulation of the immune responses 4 4

  37. Future directions. Summary CLRs are not just antigen uptakers, but modulators or even initiators of immune responses. Some of them can induce different signaling pathways by themselves. Cross-talks between CLRs and TLRs signaling remains to be fully understood (well, as everything in biology) Many CLRs act either through SYK-CARD9 or RAF1 pathways and activate NF-kB. Role of other CLR-inducible transcription factors in immune system is still unclear Thank you for you attention

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