A a Activated T-cell Mature naive T-cell Memory T-cell T-CELL DIFFERENTIATION IN THE PERIPHERY Ag...
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Activated T-cell Mature naive T-cell Memory T-cell T-CELL DIFFERENTIATION IN THE PERIPHERY Ag Ag CD4 TCR APC CD8 TCR APC CD4 TCR APC CD8 TCR APC CD4 TCR APC CD8 TCR APC Ag Naive or „resting” T cells… restless migration and recirculation, LN, lymph, blood…for several month, which is their lifespan
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Transcript of A a Activated T-cell Mature naive T-cell Memory T-cell T-CELL DIFFERENTIATION IN THE PERIPHERY Ag...
Activated T-cellMature naive T-cell
Memory T-cell
T-CELL DIFFERENTIATION IN THE PERIPHERY
Ag
Ag
CD4 TCR
APC
CD8 TCR
APCCD4 TCR
APC
CD8 TCR
APC
CD4 TCR
APC
CD8 TCR
APC
Ag
Naive or „resting” T cells… restless migration and recirculation, LN, lymph, blood…for several month, which is their lifespan
Normal tissue cells do not express MHC class IINO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokinesNO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limitedAntigen presenting cells are not activated in normal tissues
NO SIGNAL 3. for CD4+ Th activation
PERIPHERAL TISSUES TOLERIZE THEMSELVES
PERIPHERAL TOLERANCEIMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
Environmental factors and interactions with APCs initiate distinct differentiation programs in
naive T-cells
T-CELL DIFFERENTIATION
Arming of effector T cells
APC T
Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger effector
function, but…..
IL-2 EffectorT cell
Clonal selection and differentiation
How can this cell give help to or kill cells that express low
levels of B7 family costimulators?
the T cell will be activated to proliferate and differentiate under the control of
autocrine IL-2 to an effector T cell.These T cells are ARMED
ArmedEffector
T cell
CD28
Co-receptor
TcR
IL-2
Epithelialcell
NaïveT cell
Epithelialcell
Clonally selected,proliferating and
differentiatedT cell sees antigen on
a B7 negative epithelial cell
Epithelialcell
ArmedEffector
T cell
Kill
The effector programmeof the T cell is activatedwithout costimulation
This contrasts the situation with naïve T
cells, which are anergised without costimulation
Effector function or Anergy?
Virus, bacteria, protozoa, fungi
DCMΦ
NK cell
IL-12
CD8+ cytotoxic T cell
IL-12
IL-12 FAVORS POLARIZATION TO TH1-TYPE
EFFECTOR T-CELLS
Th0Th1IL-12
IFNγIFNγ
Th2
IL-2IFNγTNF-βGM-CSFIL-3
IL-4IL-5IL-10IL-13
IL-10 FAVORS POLARIZATION TO Th2
Th0IL-10
Th1
IL-2IFNγTNF-βTNF-αGM-CSFIL-3
DC
Self tissue, tumor cell
IL-10
Macrophage
Th2
IL-4IL-5IL-10IL-13
TOLERANCE
POLARIZATION OF HELPER T LYMPHOCYTES IS DIRECTED BY DENDRITIC CELL-DERIVED AND AUTOCRINE CYTOKINES AND TRANSCRIPTION FACTORS
EFFECTOR FUNCTIONS OF TH1 CELLS
Activation Killing Proliferation Feed back Entry to tissue Recruitment
Granulomas develop when intracellular pathogens resist elimination
Long term persistance of infectious agent in a separated envitonment
Responses to Mycobacterium leprae are sharply differentiated in tuberculoid and lepromatous
leprosy.
EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES
Inflammatory cytokines
CELLULAR IMMUNE RESPONSE
Anti-inflammatory cytokines
HUMORAL IMMUNE RESPONSE
IFNγ, IL-2, TNF-β/LT
Th1 Th0
IL-4, IL-5, IL-10
Th2IL-4IFNγ
Th1DC
MΦ
IFNγ
Th2 B
IL - 4
B7 expression antigen presentation
Germinal center formation
Affinity maturation
Isotype switch
Memory B cell generation
B7 expression antigen presentation
MHC-II expression antigen presentation
Mature dendritic cell
Activated macrophage
SUBSETS OF HELPER T LYMPHOCYTES COLLABORATE WITH DIFFERENT PROFESSIONAL ANTIGEN PRESENTING CELLS
CD40
CD40
CD40L
CD40L
TCR
CD4
Naive CD4+ T cell
Th0 blast
TCR
CD4
CD4
TCR
Th1 Intracellular pathogensInflammationTc activationIgG1 & IgG3 antibodiesADCC, opsonisationComplement activation
TCR
CD4 Th2Extracellular pathogensMulticellular parasitesSecretory IgA IgE, allergy
TCR
CD4 Treg
Th1 inhibitionMaintenance of immunological tolerance
CLONAL EXPANSIONDIFFERENTIATION
EPIGENETIC CHANGES, MEMORY
INTERACTIONACTIVATION
INSTRUCTION
Th17Extracellular pathogenInflammationAutoimmune diseasesAllergy
TCR
CD4
EFFECTOR HELPER T-CELLS
DC
TCR+
CD4+
CD28+
CD25+
Th1
T-bet
CCR1CCR5CXCR3
CD45RBlo
IL-12RαLAG3
Th2
GATA3
CCR4CCR3CXCR4
CD45RBhigh
IL-1R
CD30
Th17
RORγt
IL-23R
CCR6
CD127IL-7Rα↓
CTLA4B7 ligand
GITR
CD25IL-2Rα
Treg
FoxP3
CHARACTERISTICS OF EFFECTOR HELPER T LYMPHOCYTES
HOWEVER, THIS IS NOT THE END OF THE STORY… AS OF YET…CHARACTERISTICS OF EFFECTOR HELPER T LYMPHOCYTES – Th9 CELLS
Th9
PU.1 & IRF4
IL-4Rα
IL-2RγTCR+
CD4+
CD28+
CD25+
Th9 Th0 TGF-βIL-4
Other cytokines that enhance Th9 polarization:Type I IFNs , IL-1β, IL-6
IL-9IL-10CCL17CCL22
Parasitic helminth infections
Chronic allergic inflammation
Asthma
Autoimmune diseases
Annunziato and Romagnani (2009) Arthritis Research & Therapy 11:257
Neurath MF and Finotto S (2011) Cytokine Growth Factor Rev 22:83-89.
Th2 functions
Th2 cells stimulate the proliferation and differentiation of naive B cells
ISOTYPE SWITCH IN ACTIVATED B CELLS IS REGULATED BY HELPER T CELL - DERIVED CYTOKINES
ISOTYPE SWITCH IS INFLUENCED BY
site of antigen entry
tissue microenvironment
nature of professional antigen presenting cells
polarization of helper T lymphocytes
B cell
Helper T cell
IL-2IL-4IL-5
B cell proliferation and differentiation – isotype switch
IL-2IL-4IL-5 IgM
IgG
IgA
IgE
IL-2IL-4IL-6IFNγ
IL-5TGFβ
IL-4
REGULATION OF ISOTYPE SWITCH OF B CELLS
Human Ig classes and subclasses
IgM ++++ -
IgG1 ++++ +++
IgG2 + +
IgG3 +++ ++++
IgG4 +/- +
IgA - +++
IgE - +++
IgD - -
Complement activation
Classical FcR binding
Cytotoxic T-cells
PRIMING OF CD8+ CYTOTOXIC T CELLS
CD28
CD8+Tc
B7
APC
CD40
M HC I
CD4+ThCD40L
ACTIVATION
IL-2
PRIMING OF CD8+ CYTOTOXIC T CELLS THROUGH COLLABORATION OF HELPER AND CYTOTOXIC T-CELLS
1. Dendritic cells with high B7 expression activate CD8+ T cells directly
2. Dendritic cells activate CD4+ T cells, which in turn enhance the co-stimulatory activity of dendritic cells
3. Activated CD4+ T cells secrete cytokines (IL-2), which directly acts on activated CD8+ T cell
KILLING OF INFECTED CELLS BY CTL
Recognition by CTLs induces secretion of cytotoxins to the target cell
Apoptosis
Macrophage Granulocyte, macrophage
Inflammatorycytokines
IL-1TNFIL-6
a
Necrosis
DNS-ladder
PHYSIOLOGICAL AND PATHOLOGIC CELL DEATH
Apoptotic signal Cell demage
Healthy cell Necrotic cell
Apoptotic cell
Late apoptotic cell
APOPTOSIS AND NECROSIS
HIGHLY REGULATED PROCESS
1. Induction
2. Excecution
• Mitochondrial function * Activation of caspases
• Electron transport * Serine protease,calpain, proteasome
• Oxidative phosphorylateion * Redox potential
• ATP synthesis * DNA degradation (endonuclease)
MHC+peptide
TCR
CD8
FasL
Fas
Crosslinking
ICE/CASPASE
MECHANISM OF CELLULAR KILLING BY CD8+ CYTOTOXIC T LYMPHOCYTES
CD8+ T CELL TARGET CELL
H2O, Ca++, ions
Granzyme
Polymerized perforin
APOPTOSIS
Proteoglycans
CYTOKINE RELEASE
Soluble TNF
TNF-α
TNF-β/LTα
LTβLTαLTβ
Soluble FasL
FasL
CD40L
CD30L
CD27L
4-1BBL
Ox40L
TNFRI
TNFRII
LTβR
FAS
CD40
CD30
CD27
4-1BB
Ox40
RECEPTOR TRIMERIZATION
DEATH DOMAIN
TNF AND TNF RECEPTOR FAMILY MEMBERS AND THEIR LIGANDS
CTLeffector Target cell
Killedtarget cell
perforingranzyme B
Antigen recognizing receptorDeath domain
TNFRItrimerization
TNFRItrimerization
TNFRItrimerization
Fastrimerization
Fastrimerization
Fastrimerization
sFasL
sTNF
TNF
TNF
FasL
FasL
T sejt T sejt
MECHANISMS OF FAS RECEPTOR – MEDIATED PROGRAMED CELL DEATH
Cytotoxic T lymphocytes recognizevirus-infected or tumor cells
Activated cytotoxic T-lymphocyteskill virus-infected or tumor cells
CONSEQUENCE OF T CELL-MEDIATED IMMUNE RESPONSES
