MHC class II-dependent presentation€¦ · The MHC class II-like molecule HLA-DOcan subtly modulate the peptide repertoireloaded onto MHC class II molecules by HLA-DM. A new study

MHC class II-dependent presentation

1

Processazione e presentazione degli Ag extracellulari e citosolici

APC

Risposta CD4 Risposta CD8

Si No

No Si

No Si

Trasfezione

APC

Endocitosi

APC

Shock osmotico

+

+

+

I linfociti CD4 riconoscono antigeni solubili presentati in associazione con le molecole di MHC classe II

2

La processazione dell’antigene richiede la vitalità della cellula

NO PROLIFERATION

PROLIFERATION

+

+

3

La processazione dell’antigene richiede tempo

4

Antigen presentation through MHC class II molecules: antigen uptake

1^ fase

5

Antigen presentation through MHC class II molecules: antigen uptake

Consente l’accesso di antigeni o patogeni allevie intracellulari di degradazione.I meccanismi di uptake:-Fagocitosi-Pinocitosi e micropinocitosi-Fagocitosi mediata dal recettore Fc delleIg-Fagocitosi mediata dal recettore per ilcomplemento-Fagocitosi del complesso Ig-antigene-Fagocitosi tramite recettore specificodirigono l’antigene nei compartimentiintracellulari deposti alla degradazione. 6

Uptake dell’antigene

7

Antigen presentation through MHC class II molecules

2^ fase

8


3^ fase

9

The organelles of MCH class II

presentation

10

Enzimi catalitici come le catepsine

sono presenti negli endosomi

11

Enzimi catalitici come le catepsine

sono presenti negli endosomi

12

La clorochina come farmaco che inibisce l’acidificazione degli endosomi

Infettività da Leishmania

13

La processazione dell’antigene avviene nei lisosomi

NO PROLIFERATION

PROLIFERATION

14


4^ fase

15

La presentazione dell’antigene non richiede cellule metabolicamente attive

60 min

PROLIFERATION

16

La processazione e la presentazione dell’antigene sono processi diversi

+

17


+

PROCESSING 18

+

PRESENTAZIONE


19

Natura degli antigeni

Determinante antigenico od epitopo parte dell’antigene che èriconosciuto da un recettore specifico: BCR dei linfociti B (anticorpo) o dal TCR

(linfociti T)

Determinante lineare

Epitopi formati da una sequenza lineare di AA (epitopi T)

Determinante conformazionale

Epitopi formati da una sequenza di AA non vicini tra loro linearmente ma giustappposti nello spazio (epitopi B)

20

MHC class II molecules need to be protected by random engagement

The cell surface form of the invariant chain

is known as CD74.

21

Attività dell’invariant chain

The invariant chain (Ii) is a protein which binds the peptide bindinggroove of MHC II immediately following its assembly in the endoplasmicreticulum. This provides for the preservation of MHC until the vesiclefuses with MIIC and antigen peptides are introduced.

22


1^ FASE

2^ FASE

CLIP

23


24


3^ FASE

CLIPclass II-associated

invariant chain peptide25

MHC class II molecules need to be protected by random engagement

At this time, HLA-DM is free to begin functioning (Janeway et al., 2005)

2-4 hrs

26

HLA-DM assists in the removal of CLIP

27

HLA-DM is unable to allocate a peptide

28

The function of HLA-DMHLA-DM has three

main functions: 1. dissociation of

CLIP from the peptide binding groove of MHC II,

2. stabilizes and prevents degradation of the empty MHC II,

3. facilitates the binding of antigen fragments to the open, stabilized binding groove (Janeway et al., 2005).

29

HLA-DM deficiency

No known human immunodeficiency is related to the absence of HLA-DM.

Zarutskie et al. (2001) report that when HLA-DM is absent or rendered non-functional due to mutation, there is an observed increase in MHC

II:CLIP complex presented on the antigen presenting cell surface.

HLA-DM is a protein exchange molecule in MHC. Non-functional HLA-DM is unable to dissociate CLIP from MHC II which is therefore not give a chance to bind with antigen peptide and present it to

CD4 T cells to elicit an immune response.

Lich et al. (2003) suggest that changing HLA-DM concentration levels within antigen presenting cells may

cause autoantigens to present on the cell surface, potentially leading to autoimmune disorders such as type I

diabetes. 30

The peptide editing

High affinity peptides with high bindingenergy are more stable in the MHC bindinggroove while HLA-DM is present (Anderson

and Gorski, 2003).

Furthermore, HLA-DM binding to MHC IImolecules as well as catalytic peptideexchange are increased when the pH of theendosomal compartment is in the range of4.5-5.5 (Busch et al., 1998).

31

The relevance of HLA-DO

The MHC class II-like molecule HLA-DO can subtly modulate the peptide repertoire loaded onto MHC class II molecules by

HLA-DM.

A new study shows that the in vivo effect of HLA-DO is to

decrease the presentation of self peptides by dendritic cells

(DCs) to T cells, which limits autoimmune responses without

affecting general immune competence.

32

33

Altre modalità di riconoscimento dell’antigene

(presentazione non convenzionale)

1. Riconoscimento dei superantigeni

2. Presentazione MHC-indipendente

3. Presentazione attraverso la molecola CD1

4. Cross-presentazione

34







35

MHC-independent hapten presentation

36







37

CD1-mediated presentation

38

CD1 presentation: how it works

• a CD1 heavy chains are assembled in the endoplasmicreticulum (ER), where they bind the chaperones calnexin,calreticulin and ERp57. They also bind b2-microglobulin (b

2m) non-covalently in the ER.

39

40

CD1 presentation and effector activation

41







42

The meaning of cross-presentation

Until recently, MHC-I and MHC-II were thought to focus on thepresentation of peptides derived from distinct sources. MHC-I ligandswere derived from endogenous cytosolic proteins, whereas MHC-II ligandswere exogenous, encountering MHC-II molecules following endocytosis.Although this paradigm remains largely correct, we now know that bothboundaries can be crossed:-MHC-I can present peptides derived from exogenous antigens,-MHC-II can present intracellular antigens that do not come from theextracellular space.Although virtually all nucleated cells, not just professional or amateurAPCs, can present endogenous proteins on MHC-I, DCs (and to a far lesserextent MØ) can efficiently use exogenously obtained peptides for thispurpose: an event referred to as “cross-presentation.”Moreover, it is important to remember that only DCs can prime naive CD8+T cell responses, regardless of antigen source

43

Pathways for cross-presenting antigen1. Particulate antigen is

internalizedinto phagosomes

44

Pathways for cross-presenting antigen

2. phagosomes fuse with the ER

45


3 acquire the ER-resident antigen-presentation machinery (TAP, tapasin and MHC class I molecules)and Sec61 translocon. 46


B. Tapasin loads these peptides onto class I molecules, which are then transported to the cell surface.

A. internalized antigen is cleaved into peptides by proteases in the phagosome. 47


4. Internalized antigen is transferred

from the phagosome to the cytosol, possibly by

retro-translocation through Sec61

and ubiqitination by ubiquitin (Ub)-

conjugating enzymes(UBCs).

48


5. antigen is cleaved by proteasomes that associate with the phagosome membrane

49

Il sistema dei fagociti mononucleati

Le cellule dendritiche

50

Concetti generali

Antigeni ed immunogeniI fagociti mononucleati e le cellule

dendriticheIl sistema maggiore di istocompatibilità

La presentazione dell’antigene

51

La risposta immunitaria specifica si basa su :

•il riconoscimento di piccole porzionidegli antigeni (epitopi)

•l’esistenza di molecole diistocompatibilità

•la capacità delle APC di modificare(‘processare’) l’antigene 52

La risposta immunitaria specifica si basa su :

•il riconoscimento di piccole porzionidegli antigeni (epitopi)

•l’esistenza di molecole diistocompatibilità

•la capacità delle APC di modificare(‘processare’) l’antigene 53

Mechanisms of immunity

Humoral response

Antibodies

Mod from Burks AW et al, JACI 2008

B cell

Cellular response

54

APCs antigen-presenting cells (cellule accessorie)

Cellule che non esprimono recettori clonali (ovvero

recettori per l’antigene clonalmente distribuiti) ma che

partecipano attivamente all’avvio delle risposte

immunitarie specifiche ( non sono cellule

immunocompetenti)

Sono rappresentate dai fagociti mononucleati e dalle

cellule dendritiche

Hanno precipua funzione di captare gli antigeni e di

presentarli in modo appropriato ai linfociti T

55

Le cellule accessorie





immunocompetenti)


cellule dendritiche



56

Le cellule accessorie





immunocompetenti)


cellule dendritiche



57

Macrophages and dendritic cells: a bridge between innate and adaptive

immunity

The phagocyte‘eats’ a bacteria

The antigen is digestedand reaches the surface

The antigen is recognized by a T cell

The T cellactivates

The dogma of Antigen processing and association with MHC 58

Macrophages and dendritic cells: a bridge between innate and adaptive

immunity

The phagocyte‘eats’ a bacteria

The antigen is digestedand reaches the surface

The antigen is recognized by a T cell

The T cellactivates

The dogma of Antigen processing and association with MHC

The immunological

synapsis

59

Il sistema delle cellule presentanti l’antigene

M.O.

M.E.

M.A scansione

60

Le cellule presentanti

captare gli antigeni

61


62


Esprimere particolari recettori63


pattugliare l’organismo

64


65

Concetti generali




66

Mononuclear phagocyte system

circulating blood monocytes

macrophages (terminally differentiated cells)

committed myeloid progenitor cells in the bone marrow

67

Le cellule circolanti del sistema immune

Globuli bianchi % Intervallo normale (/mmc)

Neutrofili 55-70 4,500-11,000

Eosinofili 0-4 0-450

Basofili O-1 0-200

Linfociti 25-30 1,000-4,800

Monociti 10-15 0-800

68

The story comes from far

Paul EhrlichIlya Metchnikov

1908 Nobel Prize

‘….There is no need to be a doctor or ascientist to wonder why the human bodyis capable of resisting so many harmfulagents in the course of everyday life. Itis often seen that in households whereall members are exposed to the samedanger, or again in schools or troopswhere everyone lives the same life,disease does not strike everyoneindifferently. For some individuals whogo down at the attack, there are otherswho have immunity to a greater or lesserextent….’

Struggle to survive Magic bullets69

Fagociti mononucleati

70

CLP: precursore linfoide comuneCMP: precursore mieloide comuneGMP: precursore macrofagi/polimorfo nucleatiMEP: precursore eritrociti/megacariociti

Cellule di derivazione mieloide

Cellule di derivazione linfoide

Origine dei monociti/macrofagi

71

Evolutionary origin of neutrophils and monocytes

(precursore macrofagi/polimorfo nucleati)

72

Fagociti mononucleati: i monociti

Origine: cellula staminale emopoieticaCellula circolanteDiametro: 10-18 micronNucleo: grande, reniformeCitoplasma: abbondanteEmivita: 2-3 gg (midollo osseo), 2-3 gg (sangue)Funzione: immunità innatafagocitosi, attivazione dei meccanismi battericidi, produzione di citochine della flogosi;Immunità adattiva presentazione dell’antigene nel linfonodo, direzionamento delle risposte immuni

sangue

73

The monocyte/macrophage system

74

Fagociti mononucleati: i macrofagi

Origine: cellula staminale emopoieticaCellula stanzialeEmivita: molti mesiFunzione: immunità innatafagocitosi, attivazione dei meccanismi battericidi, produzione di citochine della flogosi;Immunità adattiva presentazione dell’antigene nel linfonodo, direzionamento delle risposte immuni

sangue

75

Fagociti mononucleati: i macrofagi

(10-18 micron)

sangue SNC

microglia

Cellule del Kuppfer

Fegato Milza

Macrofagi splenici

Cute

Cellule di Langerhans

Rene

Cellule mesangiali

Osso

Osteoclasto

Connettivo

Istiocita

….macrofagi alveolari, macrofagi intestinali, siti in infiammazione/infezione…….altro76

Fagociti mononucleati nei tessuti di flogosi

Cellule giganti di Langhans

77

Recettori dei monociti/macrofagi

CD marker FunzioneCD11b/CD18 Legame con particelle rivestite con C3bi

CD68 Lipoproteine a bassa densità

CD40 Costimolazione dei linfociti T

CD14Co-riconoscimento di LPS

(insieme a TLR4)

CD1 Riconoscimento di Atg lipidici



MHC classe II Presentazione dell’Atg ai linfociti T CD4+

CD16, CD32, CD64 FcgR

TLR2, TLR4, TLR8 Toll-like receptors 78

Funzioni dei monociti/macrofagi

- fagocitosi,- attivazione dei meccanismi battericidi,- produzione di citochine della flogosi e di direzionamento delle risposte immuni.

79

Innate immunity in the war against pathogens

Remove cellular debris and pathogens Stimulate repair Activate specific immunity

increase capillary permeability

Neutrophils (1h-3d)Macrophages (8h-mo)

80

Phagocytosis and diapedesis are main features of innate cells

81

Phagocytosis and diapedesis are main features of innate cells

Circulating monocyte eating malaria parasite

Neutrophil attacking bacteria

82

Fagociti mononucleati

patogeno

internalizzazione

1

2

3

4

5

83

Recettori dei monociti/macrofagi coinvolti nella fagocitosi

(uptake)

Receptor family Example Function

Scavenger SR-A Phagocytosis of bacteria and apoptotic (dying) cells

Toll-like receptors TLR4

TLR2

Response to LPS (Gram negative bacteria)

Response to peptidoglycan (bacteria)

C-type lectin –like receptors

Dectin-1 B-glucan receptor, fungal particle ingestion

Integrin CR3 Complement receptor-mediated phagocytosis

Adhesion to endothelium

Ig Superfamily FcR Antibody dependent binding/killing

84

Malattie da aumentata funzione fagocitaria

Sindrome da attivazione macrofagica (MAS)

85

http://it.wikipedia.org/wiki/File:Hemophagocytic_syndrome_-_cropped_-_very_high_mag.jpg

http://it.wikipedia.org/wiki/File:Hemophagocytic_syndrome_-_cropped_-_very_high_mag.jpg


- fagocitosi, - attivazione dei meccanismi battericidi,- produzione di citochine della flogosi e di direzionamento delle risposte immuni.

86

Prodotti dei monociti/macrofagi

Prodotto Ruolo

Citochine pro-infiammatorie

(TNF-alfa, IL-1, IL-6, IL-8)

Reclutamento dei linfociti, reclutamento di neutrofili

febbre

Citochine modulatorie

(IL-12, IFNs tipo I)

Differenziamento delle cellule T in senso TH1

Prodotti intermedi

dell’ossigeno, ossido nitrico,

enzimi lisosomiali

Uccisione dei batteri all’interno dei fagolisosomi

Chemochine

(IP-10/CXCL10, RANTES/CCL5,

MIP/CCL3)

Reclutamento delle cellule della flogosi

87

Agenti battericidi rilasciati dai monociti/macrofagi

88

Il ‘respiratory burst’

89

Immunodeficienze da alterazione della funzione monocito-macrofagicaLa Malattia Granulomatosa Cronica come esempio di alterato meccanismo

di fagocitosiGenetic deficiency of NADPH oxidase (phagocytes do notproduce the toxic oxygen derivatives of the respiratory burstand so are less able to kill ingested microorganisms and clearan infection).The most common form of CGD is an X-linked disease(inactivating mutations in the gene encoding the gp91 subunitof cytochrome b558, located on the X chromosome)unusuallysusceptible to bacterial and fungal infections, especially ininfancy. Autosomal mutations in other subunits of the NADPHoxidase can also cause chronic granulomatous disease, but canbe milder and have a later onset.

90

91

92


- fagocitosi, - attivazione dei meccanismi battericidi,- produzione di citochine della flogosi e di direzionamento delle risposte immuni.

93

Attivazione dei monociti/macrofagi

Macrofago non stimolato

Fattori umoraliAderenza alla plasticaGlicaniPMACitochineMicroorganismiLigandi di TLR

Macrofago stimolato

secrezionekillingendocitosimetabolismodimensioniVelocità di diffusioneEspressione di recettori

94


95

Citochine prodotte dai macrofagi e dalle DCs

MacrofagiCheratinociti

MacrofagiDCs

MacrofagiDCs

MacrofagiDCs

MacrofagiDCs

Linfociti

Linfociti

Fegato

Fegato

Fagociti

Cellule T indifferenziate

EndotelioVascolare

Aumenta la risposta

Induce la produzione di proteine di fase acuta

Aumenta la risposta

Induce la produzione di proteine di fase acuta

Chemoattrattante per neutrofili

Devia la risposta immunitaria in senso Th1, secrezione di citochine

Induce modificazioni nell’endotelio vascolare (espressione di selettine, tight junctions) con edema locale, aumento della permeabilità, coagulazione

96


Prodotto Ruolo

Citochine pro-infiammatorie

(TNF-alfa, IL-1, IL-6, IL-8)

Reclutamento dei linfociti, reclutamento di neutrofili

febbre

Citochine modulatorie

(IL-12, IFNs tipo I)

Differenziamento delle cellule T in senso TH1

Prodotti intermedi

dell’ossigeno, ossido nitrico,

enzimi lisosomiali

Uccisione dei batteri all’interno dei fagolisosomi

Chemochine

(IP-10/CXCL10, RANTES/CCL5,

MIP/CCL3)

Reclutamento delle cellule della flogosi

97

Modificazioni del monocita/macrofago dopo attivazione

98

Classificazione dei monociti/macrofagi

i) On the basis of their tissue distribution

ii) On the basis of their functional polarization

M1 (proinflammatory)M2 (alternatively activated) Regulatory cells in response to both

exogenous infectionsand solid tumors

Monociti/macrofagi come cellule ‘plastiche’99

Polarizzazione funzionale dei monociti/macrofagi

M1 (proinflammatory) “Classical Activation”

i) secreted molecules (IFN-γ, TNF-α) of activated T helper 1 (Th1) CD4+ lymphocytes or natural killer

(NK) cells, or ii) bacterial lipopolysaccharide (LPS) give rise to a population of macrophages with enhanced microbicidal capacity and increased

secretion of proinflammatory cytokines to further strengthen the cell-mediated adaptive immunity

CD14High CD16neg

100


M2 “Alternative Activation”

interleukin-4 (IL-4) and IL-13, signature cytokines of the CD4+ Th2 response

induce the activation of macrophages playing an important role not only in the immune

response to parasites, but also in allergy, wound healing, and tissue remodeling

• M2a (elicited by IL-4 or IL-13), • M2b (following stimulation by immune complexes in the presence of a Toll-like

receptor ligand), • M2c (when exposed to anti-inflammatory stimuli such as glucocorticoid

hormones, IL-10, or Transforming Growth Factor-β,TGF-β)

CD14low/negCD16+ 101

Regulatory monocytes/macrophages

Cells playing a pivotal role in limiting inflammation duringinnate and adaptive immune responses and producing highlevels of IL-10; unlike M2 cells, they do not contribute tothe production of extracellular matrix and express highlevels of the costimulatory molecules CD80/B7-1 andCD86/B7-2.

102

Functional differentiation processes of macrophages

103


104

Concetti generali




105

Origine dei monociti/macrofagi

CLP: precursore linfoide comuneCMP: precursore mieloide comuneGMP: precursore macrofagi/polimorfo nucleatiMEP: precursore eritrociti/megacariociti

Cellule di derivazione mieloide

Cellule di derivazione linfoide

106

Le cellule dendritiche come APC professionali

107

108

Le cellule dendritiche catturano l’antigene

dalla cute o dalle mucose e migrano nei linfonodi

109

Le cellule dendritiche catturano l’antigene

dalla cute o dalle mucose e migrano nei linfonodi

Gli antigeni presenti in circolo sono catturati dalle APC

spleniche

110

Funzioni delle cellule dendritiche (DC)

Follicular DCLangerhans’ DC

CD21+CD23+

Immature DCs patrol via the blood systems throughout the body and can invade peripheral tissues to take up antigens

from infected or dying cells via macropinocytosis, phagocytosis, and endocytosis

(Steinman et al., 1999)111

http://en.wikiversity.org/wiki/File:Follicular_Dendritic_Cell.jpg


http://images.google.it/imgres?imgurl=http://cmmg.biosci.wayne.edu/asg/dendritic.gif&imgrefurl=http://cmmg.biosci.wayne.edu/asg/dendritic.html&usg=__tng2YkwOfi-WSNM9tX6-nE-vysY=&h=844&w=701&sz=118&hl=it&start=1&itbs=1&tbnid=QsfGHHzs53keTM:&tbnh=145&tbnw=120&prev=/images%3Fq%3Dlangerhans%2Bdendritic%2Bcells%26gbv%3D2%26hl%3Dit


112

Two types of dendritic cells

113

Le cellule dendritiche (DC)

IL-12producing

IFN-a

producing

Follicular DC

-Passively present IC to B cells-are present in B cell areas of spleen, lns, MALT-Non migratory-Lack MHC II-Are CD21 and CD35 + and CD16+-Mesenchimal origin

Langerhans’ DC

-Usually reside in skin and mucosal sites-Migrate as ‘veiled cells’ to lns (paracortex)IDCs-Are highly MHC class II positive

Granuli di Birbeck

114






IL-12producing

IFN-a

producing

Follicular DC


Langerhans’ DC


115






IL-12producing

IFN-a

producing

Follicular DC


Langerhans’ DC


116





Hematopoietic progenitor cells (HPCs) in the bone marrow give rise to monocytes

circulating in the blood.

117


circulating in the blood. After interacting with inflamed endothelium,

monocytes cross the endothelial barrier and encounter a cytokine microenvironment triggered by pathogen.

118



Stromal cells (epithelial cells, keratinocytes and fibroblasts), mast cells, plasmacytoid DCs and

natural killer cells respond to microbes by secreting various cytokines. These include interleukin 15 (IL-15), transforming growth factor- (TGF-) and tumor

necrosis factor (TNF), all of which can skew monocyte differentiation into LCs.

119



LCs undergo maturation either by direct interaction with a

microbe or in response to products of

surrounding cells and migrate through

lymphatic vessels into T cell zones of draining lymph nodes, where

they secrete chemokines that attract naive T cells and induce their

proliferation and differentiation. Other

DCs, such as interstitial DCs, stimulate other

types of immune responses.

120


IL-12producing

IFN-a

producing

Follicular DC


Langerhans’ DC


CD123+BDCA-2+BDCA-4+

CD21+CD23+

121





Popolazioni principali di DCs e loro marcatori

Cellula dendritica mieloide Cellula dendritica plasmacitoide

122

Plasticità delle cellule dendritiche (DC)

CD80, CD86, ICAM

FcR, Recettoriper mannosio

MHC Classe IIEmivita circa 10 ore > 100 ore

N° molecole circa 106 circa 7x106

123

Maturation of dendritic cells causes acquisition of novel markers

124

http://www.ncbi.nlm.nih.gov/books/NBK27118/figure/A1040/?report=objectonly






• CD14+/- (se da Mo.)• CD40+• MHC II+• CD83-• CD80+• CD86+• CCR5+• CCR6+• CXCR4+/-• TREM-2 (MDC)• TLR9 (PDC)• TLR-8 (MDC)• TLR7 (MDC, PDC)• TLR-4, TLR-2 (MDC)

• CD14-

• CD40+++

• MHC IIhi

• CD83+

• CD80+++

• CD86+++

• CCR5-

• CCR6-

• CCR7+

• CXCR4+

Monitoraggio del fenotipo:iDC e mDC

iDC mDC

125

CD86

Medium LPS 10 ng/ml LPS 100 ng/mlCD14-der D

CCD34-der D

CCD34-der(+

IL-4) D

CC

D8

0

22.7 17.3

9.4

11.3 86.5

1.1

30.4 67.3

0.4

52.9 29.5

2.9

10.9 34.5

13.9

13.4 30.1

5.0

7.4 39.0

4.0

50 43.8

3.4

12.6

30.813.5

126

CD1a

4° C

30 min 4 hCD14-der D

CCD34-der D

CCD34-de

r(+

IL-4) D

C

0.3 0.1

0.4

33.4 27.0

7.4

27.7 22.1

11.9

0.1 0.1

0.4

49.8 17.3

2.5

69.2 18.4

1.2

10.8 44.6

6.8

32.0 45.9

3.1

BS

AF

IT

C

37° C

127

Dendritic cells as plastic APCs

128

Regulatory dendritic cells

129

Regulatory dendritic cells

130

Cancer immunotherapy: optimization of cellular vaccines

131

DC2 matura

PRECURSORI DELLE DC E LORO MATURAZIONE IN VITRO

In vitro

In vivo

HPC CD34+

- Midollo osseo

- Sangue di cordone ombelicale

- Sangue periferico

Cellula plasmocitoide

CD123+ BDCA2+ CD4+

- Timo - Linfonodi

- Tonsille - Sangue periferico

Monocita (CD14+)

- Sangue periferico

DC1 immatura DC2 immatura

Cellula di LangerhansDC1 matura

GM-CSF

TNF-a

SCF, FlT3-L

IL-3GM-CSF

IL-4

TGF-bTNF-a or

LPS or

MCM or

CD40-L

CD40-L or

CpG

CD34low+ CLA+

GM-CSF, G-CSF

SCF, FlT-3,

IL-3, IL-7

Linea mieloide Linea linfoide

132

Provenge as the only commercially available dendritic-based vaccine

133

134

135

136

137

Documents

MHC class II-dependent presentation€¦ · The MHC class II-like molecule HLA-DOcan subtly modulate the peptide repertoireloaded onto MHC class II molecules by HLA-DM. A new study