Corso di Immunologia e Immunopatologia - II anno Lezione 16/04/2012

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2 Corso di Immunologia e Immunopatologia - II anno Lezione 16/04/2012 marco.cippitelli@uniroma1.it cippiskype APCs, DCs recettori e maturazione. Il materiale presente in questo documento viene distribuito esclusivamente ad uso interno e per scopi didattici.

3 THE SPECIALIZED ANTIGEN-PRESENTING CELLS

4 L ETEROGENEITA DELLE CELLULE DENDRITICHE Le cellule DC comprendono una famiglia di leucociti che condividono una morfologia simile e con il potenziale di interagire anche con i linfociti T vergini. Sono fondamentali nel determinare il tipo di risposta immunitaria Activation of immune response Maintenance of tolerance to self antigens Questa funzione richiede la loro maturazione/attivazione.

5 LE CELLULE DENDRITICHE

6 DENDRITIC CELL - T LYMPHOCYTE INTERACTION

7 LE CELLULE DENDRITICHE

8 THREE SIGNALS ARE REQUIRED FOR LYMPHOCYTE ACTIVATION Cytokines 3 Costimulatory molecules

9 DENDRITIC CELLS DIFFER IN REGARD: Differentiation state Anatomical localization and migration pattern Repertoire of PRR (Pattern Recognition Receptors) including C-type lectin, mannose receptors and TLRs Cytokine profile

10 HUMAN DC SUBSETS IN VIVO

11 La distribuzione tissutale e la migrazione delle diverse DC

12 LA CELLULA DI LANGERHANS

13 LE CELLULE DI LANGERHANS DELL EPIDERMIDE Costimolo

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15 LA MATURAZIONE DELLE CELLULE DENDRITICHE

16 LA MATURAZIONE DELLE CELLULE DENDRITICHE

17 DENDRITIC CELLS INITIATE ADAPTIVE IMMUNE RESPONSES Figure 1-13

18 LA MATURAZIONE DELLE CELLULE DENDRITICHE

19 PATHOGEN COMPONENTS ACTIVATE IMMATURE DC STIMULATING: MIGRATION EXPRESSION OF COSTIMULATORY MOLECULES

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21 DENDRITIC CELLS AS SENSORS OF LIFE, DEATH AND DANGER RECETTORI DELLE DC

22 I PRINCIPALI RECETTORI DELLE DC RECETTORI TOLL-LIKE RECETTORI LECTINICI (ligandi di natura oligosaccaridica) LE INTEGRINE BETA-2: CR3 (recettori per componenti del complemento) CR4 I RECETTORI Fc Ig

23 LABOR DIVISION TLR family mainly acts to alert DC and induce their maturation C-type lectin family operate as costituents of antigen capture, degradation and loading of MHC molecules (endocytic receptors)

24 C-TYPE LECTINS AND TOLL-LIKE RECEPTORS: PATHOGEN RECEPTORS ON DENDRITIC CELLS

25 C-TYPE LECTINS AND TOLL-LIKE RECEPTORS: PATHOGEN RECEPTORS ON DENDRITIC CELLS

26 C-TYPE LECTIN RECEPTORS (CLRs) CLR are abundantly expressed by immature dendritic cells in peripheral tissues The expression of most CLR is down-regulated upon dendritic cell maturation

27 C-TYPE LECTIN RECEPTORS

28 C-TYPE LECTIN RECEPTORS

29 Le FUNZIONI di DC-SIGN Attivazione dei linfociti T Cattura dell Ag Il ligando di DC-SIGN è ICAM-3 Recettore solubile Adesione/migrazione

30 MUCOSAL TRANSMISSION OF HIV

31 MUCOSAL TRANSMISSION OF HIV

32 LABOR DIVISION TLR family mainly acts to alert DC and induce their maturation C-type lectin family operate as costituents of antigen capture, degradation and loading of MHC molecules (endocytic receptors)

33 Christiane Nüsslein Volhard, Premio Nobel 1995

34 Christiane Nüsslein Volhard, Premio Nobel 1995 TOLL

35 THE TOLL-LIKE RECEPTOR FAMILY Modlin RL and G Cheng Nature Med 2004

36 THE VERY ANCIENT FAMILY OF TOLL-LIKE RECEPTORS REGULATES INNATE IMMUNITY and RECOGNITION Kimbrell DA, Beutler B. Nat Rev Genet. 2001

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39 Toll-like receptors recognize a range of pathogen-derived products

40 NUCLEIC ACID RECOGNITION PATHWAYS IN INNATE IMMUNE CELLS Wagner H and Bauer S J Exp Med 2006

41 INNATE IMMUNE DETECTION OF MICROBES OCCURS AT DISTINCT CELLULAR LOCATIONS. TLR5 TLR1/2/6 TLR4 1. Extracellular membrane-spanning sensors T T T ADAPTORS 2. Vesicular membrane spanning sensors P Nalps 3. Intracellular sensors TLR3 TLR7/8/9 IPAF T T ADAPTORS C RIG1/ Mda5 C C Nod1/2 ASC Caspase-1 ADAPTORS nucleus Adapted from Werst C et al, Cell Death and Differentiation 2006

42 DC POPULATIONS EXPRESS NON-OVERLAPPING SETS OF TLRs TLR 1,2,6, 4, 5,8 TLR 1,2,6, 5, 3,8 TLR 7, 9 TLR 1,2,6, 3,9 TLR 1,2,6, 5, 3, 7, 9

43 TLRs AT THE INTERFACE BETWEEN INNATE AND ADAPTIVE IMMUNE RESPONSE pathogen recognition TLR capture antigen presentation APC TCR T T cell activation and polarized response Co-stimulatory molecules Pro-inflammatory cytokines Innate immunity Adaptive immunity

44 LA TRASDUZIONE DEL SEGNALE DEI RECETTORI TLR

45 LA TRASDUZIONE DEL SEGNALE DEI RECETTORI TLR

46 LA TRASDUZIONE DEL SEGNALE DEI RECETTORI TLR

47 THE SIGNALLING PATHWAYS OF TLR-4