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Transcript
T-CELL DIFFERENTIATION IN THE PERIPHERY
CD8 TCR
CD8 TCR
CD8 TCR
CD4 TCR
CD4 TCR
CD4 TCR
APC
APC
APC
Ag
Ag
Ag
APC
APC
APC
Memory T-cell
Activated T-cell
Mature naive T-cell
Naive or „resting” T cells… restless migration and recirculation, LN, lymph, blood…for several
month, which is their lifespan
PERIPHERAL TOLERANCE
IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
Normal tissue cells do not express MHC class II
NO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules and do not
produce T cell differentiating cytokines
NO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limited
Antigen presenting cells are not activated in normal tissues
NO SIGNAL 3. for CD4+ Th activation
PERIPHERAL TISSUES TOLERIZE THEMSELVES
T-CELL DIFFERENTIATION
Environmental factors and interactions with APCs
initiate distinct differentiation programs in
naive T-cells
Arming of effector T cells
Clonal selection and differentiation
APC
T
Activation of NAÏVE T cells by signal 1 and
2 is not sufficient to trigger effector
function, but…..
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
IL-2
Effector
T cell
How can this cell give help to
or kill cells that express low
levels of B7 family
costimulators?
Effector function or Anergy?
Clonally selected,
proliferating and
differentiated
T cell sees antigen on
a B7 negative epithelial cell
The effector programme
of the T cell is activated
without costimulation
Armed
Effector
T cell
Armed
Effector
T cell
IL-2
This contrasts the
situation with naïve T
cells, which are anergised
without costimulation
Naïve
T cell
CD28
TcR
Co-receptor
Kill
Epithelial
cell
Epithelial
cell
Epithelial
cell
IL-12 FAVORS POLARIZATION TO TH1-TYPE
EFFECTOR T-CELLS
Virus, bacteria,
protozoa, fungi
NK cell
IL-12
IFNγ
Th1
IL-2
IFNγ
TNF-β
GM-CSF
IL-3
DC
MΦ
CD8+ cytotoxic T cell
IL-12
IFNγ
IL-12
Th0
Th2
IL-4
IL-5
IL-10
IL-13
IL-10 FAVORS POLARIZATION TO Th2
Self tissue, tumor cell
Macrophage
DC
Th1
IL-2
IFNγ
TNF-β
TNF-α
GM-CSF
IL-3
IL-10
Th0
IL-10
Th2
IL-4
IL-5
IL-10
IL-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
Th1
Th0
IFNγ
Th2
IL-4
IL-4, IL-5, IL-10
IFNγ, IL-2, TNF-β/LT
Inflammatory cytokines
Anti-inflammatory cytokines
CELLULAR IMMUNE RESPONSE
HUMORAL IMMUNE RESPONSE
SUBSETS OF HELPER T LYMPHOCYTES COLLABORATE WITH DIFFERENT
PROFESSIONAL ANTIGEN PRESENTING CELLS
B7 expression  antigen presentation
Germinal center formation
Th2
CD40L CD40
B
Affinity maturation
Isotype switch
IL - 4
Th1
CD40L
IFNγ
CD40
Memory B cell generation
DC
MΦ
B7 expression
 antigen presentation
MHC-II expression  antigen presentation
Mature dendritic cell
Activated macrophage
Th1
EFFECTOR HELPER T-CELLS
CD4
TCR
CD4
Naive CD4+ T cell
TCR
CD4
CD4
TCR
TCR
DC
INTERACTION
ACTIVATION
INSTRUCTION
CD4
TCR
Th0 blast
CD4
TCR
CLONAL EXPANSION
DIFFERENTIATION
Intracellular pathogens
Inflammation
Tc activation
IgG1 & IgG3 antibodies
ADCC, opsonisation
Complement activation
Th2
Extracellular pathogens
Multicellular parasites
Secretory IgA
IgE, allergy
Th17
Extracellular pathogen
Inflammation
Autoimmune diseases
Allergy
Treg
Th1 inhibition
Maintenance of
immunological tolerance
EPIGENETIC CHANGES,
MEMORY
CHARACTERISTICS OF EFFECTOR HELPER T LYMPHOCYTES
CCR1
CCR5
CXCR3
Th1
T-bet
CCR6
CD45RBlo
IL-12Rα
LAG3
Th17
IL-23R
RORγt
TCR+
CD4+
CD28+
CD25+
CD25
IL-2Rα
CD127
IL-7Rα↓
CCR4
CCR3
CXCR4
Th2
GATA3
Treg
CD45RBhigh
FoxP3
IL-1R
CD30
GITR
CTLA4
B7 ligand
HOWEVER, THIS IS NOT THE END OF THE STORY… AS OF YET…
CHARACTERISTICS OF EFFECTOR HELPER T LYMPHOCYTES – Th9 CELLS
IL-2Rγ
Th9
TCR+
CD4+
CD28+
CD25+
IL-4Rα
PU.1 & IRF4
Th0
TGF-β
IL-4
Th9
IL-9
IL-10
CCL17
CCL22
Parasitic helminth
infections
Chronic allergic
inflammation
Asthma
Autoimmune diseases
Other cytokines that enhance Th9 polarization:
Type I IFNs , IL-1β, IL-6
Annunziato and Romagnani (2009) Arthritis Research & Therapy 11:257
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
REGULATION OF ISOTYPE SWITCH OF B CELLS
IL-2
IL-4
IL-5
Helper T cell
IL-2
IL-4
IL-5
IL-2
IL-4
IL-6
IFNγ
IL-5
TGFβ
IgM
IgG
IgA
B cell
IL-4
B cell proliferation and differentiation – isotype switch
IgE
Human Ig classes and subclasses
Complement activation
Classical
FcR binding
IgM
++++
-
IgG1
++++
+++
IgG2
+
+
IgG3
+++
++++
IgG4
+/-
+
IgA
-
+++
IgE
-
+++
IgD
-
-
Cytotoxic T-cells
PRIMING OF CD8+ CYTOTOXIC T CELLS
PRIMING OF CD8+ CYTOTOXIC T CELLS THROUGH COLLABORATION OF
HELPER AND CYTOTOXIC T-CELLS
ACTIVATION
CD40L
CD40
APC
CD4+
Th
IL-2
B7
MHC I
CD28
CD8+
Tc
1. Dendritic cells with high B7
expression activate CD8+ T cells
directly
2. Dendritic cells activate CD4+ T cells,
which in turn enhance the costimulatory 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
PHYSIOLOGICAL AND PATHOLOGIC CELL DEATH
Apoptotic signal
Cell demage
Apoptosis
Necrosis
DNS-ladder
Inflammatory
cytokines
IL-1
TNFa
IL-6
Macropha ge
Granulocyte, macrophage
APOPTOSIS AND NECROSIS
Healthy cell
Necrotic cell
Late apoptotic cell
Apoptotic cell
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)
MECHANISM OF CELLULAR KILLING BY CD8+ CYTOTOXIC T
LYMPHOCYTES
H2O, Ca++, ions
Proteoglycans
Polymerized perforin
Granzyme
CYTOKINE RELEASE
CD8
APOPTOSIS
TCR
MHC+
peptide
ICE/CASPASE
Crosslinking
FasL
Fas
CD8+ T CELL
TARGET CELL
TNF AND TNF RECEPTOR FAMILY MEMBERS AND THEIR LIGANDS
TNFRI
Soluble TNF
TNF-α
TNFRII
TNF-β/LTα
LTβR
LTβ
LTα
LTβ
RECEPTOR
TRIMERIZATION
FAS
DEATH DOMAIN
Soluble FasL
FasL
CD40
CD40L
CD30
CD30L
CD27
CD27L
4-1BB
4-1BBL
Ox40
Ox40L
MECHANISMS OF FAS RECEPTOR – MEDIATED PROGRAMED CELL
DEATH
TNFRI
trimerization
Fas
trimerization
TNF
CTL
effector
FasL
Killed
target cell
Target cell
perforin
gra nzym e B
TNFRI
trimerization
TNF
TNFRI
trimerization
T sejt
sTNF
T sejt
sFasL
FasL
Fas
trimerization
Death domain
Fas
trimerization
Antigen recognizing receptor
CONSEQUENCE OF T CELL-MEDIATED IMMUNE RESPONSES
Cytotoxic T lymphocytes recognize
virus-infected or tumor cells
Activated cytotoxic T-lymphocytes
kill virus-infected or tumor cells