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RIC

Celulele NK

Apararea antivirala

Apararea antiinfectioasa
Organism

Reprez

Fag
(II)

VIRUSURI Grip
Oreion
Pojar
Rinovirus

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BACT
Listeria m
INTRA
Legionella
CELULARE Mycobact
Ricketsia
BACT
Staph spp
EXTRA
Strep spp
CELULARE Neisseria
Salmonella

CK
(II)

NK
(II)

Complement

Ac
neutral

CTL

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IFN

Apararea anti-virala

Raspunsul Imun mediat Celular


Scop:
1. Apararea impotriva microbilor cu habitat
intracelular:
Celule fagocitare
Celule non-fagocitare =>
Recunoasterea & distrugerea celulor expun :

AgEndogene+MHC I (infectie/ tumorale): cel singenice


(proprii/self)
Ag + MHCI : Cel allogenice (non-self) (grefe tisulare /organ)

Mecanismul de distrugere: Citotoxicitate

RIC: celule
I. Celule efectoare

1. specifice:T CD8+ (citotoxice, LTC)


2. ne-specifice: Natural killer (NK)

APC

Roluri:

Recunoasterea celulelor-tinta
(mecanisme diferite)
Distrugerea celulelor-tinta
(mecanisme similare)

II. Celule Auxiliare:


1.
APC ( TCD4)
2.
T CD4 (TH) TCD8 (M)
Rol: activarea completa a LT CD8

Apararea antivirala
innascuta si adaptata

RI antiviral:
Innascut si Adaptat

Interferoni
Structura Prot & Gp familii:
Tip I (, , ,,) -secretati de

celulele infectate viral


CD,
Leucocite ()
Fibroblaste ()

Tip II ( ) secretati de

celulele imune efectoare RIC: TH1, LTC, NK


APC: profesionale

Stimuli:

Infectia virala ( , )

Status inflamator ()

Receptori:

RTip I (com) IFN-R1 & R2


R Tip II () IFN-R1 & R2

Efecte: Similare

+ transcriptiei gene ~IFN


+genei ds-RNA PKR (enzima) =>
blocarea sintezei proteinelor virale

STAT,signal transducer & activator of transcription


IFN-regulatory factor 9=

ISRE-IFN-stimulated response elements

Principalele functii ale familiei


IFN
1. + celulele sanatoase

+ genele secretie PKR


blocarea replicarii virale in
celulele sanatoase

2. activeaza M
3. mobilizeaza NKs

Efectele
anti-virale
ale IFN /

PKR

2. AutoFosforilare
PKR

1.fosforilare

PKR=protein kinase
(dsRNA-dependent)
eIF2= subunit of eukaryotic initiation factor 2

Apararea antivirala innascuta si adaptata

remember:

RIC: celule

I. Celule efectoare

1. specifice:T CD8+ (LTC)


2. ne-specifice: Natural killer
(NK)

APC
1

Roluri:

Recunoasterea celulelor-tinta
(mecanisme diferite)
Distrugerea celulelor-tinta
(mecanisme similare)

II. Celule Auxiliare:


procesare Ag MHC I, II
1. APC ( TCD4)
2. TCD4 (TH) TCD8
Rol: activarea completa a LT CD8

remember:

I. Celulele imunitatii innascute


Hematopoiesis

remember:

Celule NK
I linie de aparare impotriva:
1. Celulelor infectate viral
2. Celulelor tumorale
3. Altor patogeni intracelulari
Implicate in:
4. Respingerea grefei
5. Autoimunitate

6. Avortul Spontan

NK Cell

Tumor Cell

Celule NK: caracteristici (I)


Denumirea:
Localizari:

semnalizeaza functia citotoxica


circulante: 5-15% populatia Lf

organe: splina, ficat, uter

Identificare: CD3 CD56 CD16


CD3 implicat in transducerea semnalului prin TCR
CD56 ? CAM
CD16 receptor tip Ig FcRIIIA
(recunoaste Fc IgG fctie efectoarea NK (ADCC)

Celule NK: caracteristici (II)


3 Subseturi

Majoritatea: CD3- CD56dimCD16+

Contin perforine si granzyme citolitica


Moduleaza secretia CK

Minoritate: CD3_CD56brightCD16-

Secreta cant CK (IFN,TNF, IL-10)


Activitate citolitica redusa

Rare: CD3-CD56-CD16+

Activitate citolitica foarte redusa


Secreta numai cant scazute de CK
? Precursori CD3- CD56dimCD16+

Celule NK: caracteristici (III)


Receptori*
caracteristici

Kill Activator Receptors (KAR)


Kill Inhibitor Receptors (KIR)

Recunosc:

celulele proprii infectate


celulele proprii modificate
Lig (P/DAMP) cel proprii modificate (KAR)
Lig (MHC I) cel proprii nucleate N (KIR)

Recunoastere:
(Nespecifica)
Activare:

Actiuni:

echilibru semnalele activatoare ~ inhibitoare

liza celulelor-tinta
secreta CK implicate in apararea antivirala

Celule NK: importanta


RIC mediat NK n infeciile cu:
1.
2.
3.
4.

Arenavirus (vs coriomeningitei limfocitare)


Virusul herpetic (vs Herpes simplex)
Ortomixovirusuri (vs gripal)
Picornavirus (vs Coxsackie)

Timpul de raspuns:
Rspunsurile maxime celule NK: ore / zile
Rspunsurile maxime celule T & B: > 7zile

Receptori
NK

Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science. 331, 44-49 (2011).

Ce recunosc NK?
Prezenta & absenta Selfului : MHC I: HLA-A, -Bw, -Cw, -G
Self-ul indus/ modificat: proteine care semnalizeaza stresul celular:
HSP,
MIC-A, MIC-B, (MHC I chain-related proteins type A, B)

Fam Receptori NK

Natura
Moleculara

Liganzi

Coresp.
soarece

KIR (killer Ig-like R) Superfamilia Ig

HLA-A, -Bw, -Cw, -G gp49

ILT/LIR

Superfamilia Ig

HLA Cls Ia (-G)

LRC

CD94/NKG2 (KLR)

C-type lectin-like

HLA Cls Ib (-E)

NKC / Ly49

KAR (NKG2D, KLRK1) C-type lectin-like MIC A,B & MHC I-like NKG2D
NCR

Superfamilia Ig

Hemaglutinine Virale,

NCR

Receptorii Inhibitori ai NK
(KIR*)

Dupa Abas at al. 2012 Elsevier/Saunders

Caracteristic: ITIM =Immunoreceptor Tyrosine based Inhibitor motif

I. C-type lectin:
CD94 ( NKG2A)
Ligand: MHC I
Semnal ITIM

II. Ig-like family:


KillerIg-like R*:
Ligand: MHC I I
SemnalITIM

Mecanisme de Activare ai
KIR
Celulele nucleate self N (sanatoase)

Legarea ligandului (MHC I) la receptorul


NK Da semnal inhibitor
NK recunoaste tinta drept celula self+
sanatoasa
NK se detaseaza fara sa lizeze celula

Celule infectate/transformate malign

Pierderea ligandului inhibitor (MHC I) Nu


semnal inhibitor
NK recunoaste tinta drept celula self
absent/missing self
DA liza celulara: degranulare
perforinei & granzimelor

Receptorii Activatori ai NK
(KAR)

Dupa Abas at al. 2012 Elsevier/Saunders

Caracteristic: ITAM
I. C-type lectin:
NKG2D:
Leaga MIC-A,B
Semnal ITAM

II. Ig-like family:


CD16 (Fc RIIIa)
Leaga IgG
SemnalITAM*

Mecanisme de Activare ai
KAR

Celulele nucleate self N (sanatoase)

LIGAND: molecule stres =>


Fara ligand recunoscut de KAR Fara
semnal activator
NK recunoaste tinta ca fiind N,
sanatoasa
NK se detaseaza fara sa lizeze celulatinta

Celule infectate/transformate malign


Recunoasterea ligandului stres Da
semnal activator
NK recunoaste tinta ca fiind

self indus: ( MIC-A, B, HSP)


non-self (proteine virale + molecule MHClike)
DA liza celulara: degranulare perforina &
granzime

Recunoastere
celule
infectate
(maligne)

Asocierile cu Boala
ale Combinatiilor Alelice KIR & HLA
Disease
AIDS

KIR
3DS1
3DS1 homozygous

HLA
HLA-Bw4Ile80
No HLA-Bw4Ile80

Disease progression
Decreased
Increased

Proposed contribution by KIRs


Less inhibition
More inhibition

HCV infection

2DL3 homozygous

HLA-C1 homozygous

Decreased

Less inhibition

3DS1

Increased

Less inhibition

No 3DS1

HLA-C1 homozygous
and no HLA-Bw4
HLA-C2 and/or HLA-Bw4

Decreased

More inhibition

Malignant melanoma

2DL2 and/or 2DL3

HLA-C1

Increased

More inhibition

Psoriatic arthritis

2DS1 and/or 2DS2

HLA-C1 homozygous or
HLA-C2 homozygous

Increased

Less inhibition

Type I diabetes

2DS2

HLA-C1 and no HLA-C2,


no HLA-Bw4

Increased

Less inhibition

Preeclampsia

2DL1 with fewer


2DS (mother)

HLA-C2 (fetus)

Increased

More inhibition

Cervical neoplasia
(HPV-induced)

Rajagopalan, S., Long, E. Understanding how combinations of HLA and KIR genes influence disease. J. Exp. Med. 201, 1025-1029 (2005).

Mecanismele efectoare ale NK

I. Citotoxicitate
A.

B.
C.

Directa:

Liza osmotica a celulei tinta (perforine)


Apotoza celulei-tinta (granzime B)

Apotoza celulei-tinta (IFN +FasL; TRAIL=> +

Indirecta:
caspaze)

*Mecanism mediat de Ac (ADCC: Ab dependent cellular


cytotoxicity)*

Stimulata de CK II:
IL-12 (GF)
IL-15 (GF)
IL-18
IFN /

Mecanismele citotoxice ale NK


Citotoxicitate directa:
Etape:
1. Adeziunea intercelulara
2. Polarizarea citoscheletului
3. Degranularea veziculelor
litice
4. Liza celulei -tinta

-Degranularea
1. Adeziunea
inter-celulara,
2. polarizarea
citoscheletului

1.Adeziunea ,
2.Polarizarea
citoschelet
3. Liza eficienta a
celulei-tinta

Mecanismele citotoxice ale NK

Smyth, M. J. et al. Activation of NK cell cytotoxicity. Mol. Immunol. 42, 501510 (2005).

Mecanismele Efectoare ale NK (II)

Dupa Abas at al. 2012 Elsevier/Saunders

II. Secretie de citokine:


1. +Activitate antivirala: secretia de IFNs
2. Amplifica activarea M
3. + mobilizarea NK

Mecanisme virale de evadare


1. Variatia antigenica:

Virusul gripal, HIV, rinovirus

2. Productia de modulatori imuni:

Receptori solubili ai CK actioneaza ca momeli


=> blocrea actiunii CK (poxvirusurile)
CK imunosupresoare (ex EBV prod IL-10)

3. Angajarea unor cai de inhibare:


LCMV (oareci), HIV (oameni): PD-1

4. Infecia celulor sistemului imunitar


HIV

5. Inhibarea procesarii Ag pe calea MHC I

Diferite mecanisme: CMV, HSV, EBV, adenovirus

2. Inhibarea procesarii Ag
pe calea MHC I