Download 7 T cell

ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS
THAT EXPRESS MHC MOLECULES
!!
T
II
soluble Ag
Native
membrane Ag
Cell surface MHCpeptide complex
Peptide
antigen
Cell surface
peptides
APC
APC
APC
No T-cell response
T-cell response
MHCI
Expressed by all nucleated cells
STRUCTURE OF CLASS I MHC MOLECULES
PEPTIDE
2
3
1
2m
!
!
MHCII
!
!
Expressed by professional antigen presenting cells
Macrophage, dendritic cell, B cell
STRUCTURE OF CLASS II MHC MOLECULES
PEPTIDE
1
1
2
2
RECOGNITION OF EXOGENOUS AND ENDOGENOUS
ANTIGENES BY T-LYMPHOCYTES
!
!
Tc
Th
TCR
TCR
Peptide
Peptide
MHCI
MHCII
Exogenous Ag
Endogenous
Ag
APC
Peptides of endogenous proteins
(virus, tumor) bind to class I MHC
molecules presented to cytotoxic
T cells
Peptides of exogenous proteins
(toxin, bacteria, allergen) bind to class
II MHC molecules presented to helper
T cells
B cell epitop
T cell epitop
B cells recognize:
T cells recognize:
proteins
polysaccharides
lipids
DNS
steroids
drugs, etc
peptides (8-23 amino acid)
Tissue or soluble antigens
!
!
only when these peptides are
presented by MHC molecules
on APC cells
TCR
!!
T cell receptor (TCR)
The TCR, which recognizes peptide antigens displayed by MHC molecules
BCR
V
s
VL
sH
s
s
s
s
s
C
sH1
s
CLs
s
s
s
s
s
s
s
s
s
ss
ss
CH2ss ss
CH3ss
s
s
:
•membrane-bound heterodimer composed of an α chain and a β chainm, each chain
containing one variable (V) region and one constant (C) region Both the α chain and
the β chain of the TCR participate in specific recognition of MHC molecules and
bound peptides
s
CD3
jeltovábbítás
CD3
jeltovábbítás
TCR is similar to BCR, but:
TCRs only function as membrane
receptors
B cell
TCR
T cell
!!
Plasma cell
TCR has single antigen recognition unit
cells
B and TTcell
functions
T cell migration and activation
A T-cell precursors migrate from the
bone marrow to thymus
Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid
organs, and present foreign antigens to naive T cells.
T cell response requires the DC-mediated antigen prezentation in the secondary
lymphoid organs
!
ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS
THAT EXPRESS MHC MOLECULES
!!
T
II
soluble Ag
Native
membrane Ag
Cell surface MHCpeptide complex
Peptide
antigen
Cell surface
peptides
APC
APC
APC
No T-cell response
T-cell response
CHARACTERISTICS OF T-CELL ANTIGEN RECOGNITION
1. The TCR is not able to interact directly with soluble or cell-bound antigen
2. T-cell activation can be induced by antigen in the presence of acessory
cells, only
3. T-cells recognize virus-infected cells
ACCESSORY CELL
ANTIGEN BINDING
NO INTERACTION
V
T-CELL
ACTIVATION
C
Antigen receptor
B-CELL
/
T-CELL
THE IMMUNOLOGICAL SYNAPSE
APC
T
THE INTERACTION OF T CELLS AND ANTIGEN
PRESENTING CELLS
interaction
recognition
1
2
3
4
5
6
stabilization
7
8
separation
Negulescu P.A. et. al. Immunity 4: 421-430, 1996
(review)
Phases of T cell response
!
Effector functions of T cells:
1. cytotoxicity
2. citokine production
Effector T cells
Cytotoxic T cells
Against
Helper T cells
intracellular
intra and extracellular
pathogens
Antigen prezentation activates T cells, both cytotoxic and helper T
cells require antigen presentation
RECOGNITION OF EXOGENOUS AND ENDOGENOUS
ANTIGENES BY T-LYMPHOCYTES
!
!
Tc
Th
TCR
TCR
Peptide
Peptide
MHCI
MHCII
Exogenous Ag
Endogenous
Ag
APC
Peptides of endogenous proteins
(virus, tumor) bind to class I MHC
molecules presented to cytotoxic
T cells
Peptides of exogenous proteins
(toxin, bacteria, allergen) bind to class
II MHC molecules presented to helper
T cells
CITOTOXIC T LYMPHOCYTES
cytotoxic T cells
Infected or tumoric cells
Cytotoxic T-cells
KILLING OF INFECTED CELLS BY CTL
Recognition by CTLs
induces secretion of
cytotoxins to the
target cell
KILLING OF TUMOR CELLS BY CTL
Cytotoxic T lymphocytes recognize
virus-infected or tumor cells
Activated cytotoxic T-lymphocytes
kill virus-infected or tumor cells
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
Healthy cell
Necrotic cell
Late apoptotic cell
Apoptotic cell
HIGHLY REGULATED PROCESS
1. Induction
2. Excecution
•
Mitochondrial function 
•
Electron transport 
•
Oxidative phosphorylateion 
•
ATP synthesis 
* Activation of caspases
* Serine protease,calpain, proteasome
* Redox potential
* DNA degradation (endonuclease)
MECHANISM OF CELLULAR KILLING BY CD8+
CYTOTOXIC T LYMPHOCYTES
H2O, Ca++, ions
Polymerized perforin
Granzyme
CYTOKINE RELEASE
CD8
APOPTOSIS
TCR
MHC+
peptide
ICE/CASPASE
Crosslinking
FasL
Fas
CD8+ T CELL
TARGET CELL
!!
Activation of helper T cells results in cytokine
production
THE MOST IMPORTANT FEATURES OF CYTOKINES
 The most important mediators of indirect cell communication in the
immune system („hormones” of the immune system).
 Act in low concentrations.
Cytokines can affect in an autocrine way, in a paracrine way,
or in an endocrine way 
pleiotropic effect.
 Cytokines can act by synergistic or antagonistic ways to each other.
A given cell may by affected by many cytokines resulting in the
same effect  redundant effect.
-
The responsiveness of the given cell is based on the expression of
cytokine-specific receptors.
!!
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
The three types of effector T cell produce distinct
sets of effector molecules.
TH1 sejtek
Effector function of TH1 cells
Activation of CD8
cytotoxic T cells
Makrofág
aktiváció,
baktérium ölés
Krónikusan
fertőzött
makrofágok
elpusztítása,
baktérium pusztítás
T sejt osztódás,
effektor sejtek
Makrofág
differenciáció a
csontvelőben
Endotél
aktiváció,
makrofág
migráció
Makrofág
akkumuláció
TH1
Th2 functions
Defence against extracellular pathogens
bacteria, fungi, parasites
Th2 cells stimulate the proliferation and differentiation of
naive B cells
Cytotoxic+ T-cells
!
EFFEKTOR T LYMFOCYTES
!!
MHCI is present in all the nucleated cells
Intracellular pathogens can be presented on all the cells
Any cell is infected, can be killed by cytotoxic T cells
MHCII present extracellular antigens to helper T cells.
Helper T cells direct the immun eresponse by the
pruduced cytokines.
!
!
T helper cells (TH cells) assist other white blood
cells in immunologic processes
Cytotoxic T cells (TC cells, or CTLs) destroy
intracellularly infected cells and tumor cells
Fin
Mi dönti el, hogy egy Th sejt milyen típusú
!
Az antigénprezentáció mellett megjelenő citokin
termelés meghatározza az immunválasz irányát
Key step in Th1 differentiation is
the production of IL-12 by
Macrophages or DCs that will
result in the INF-γ production by
the T cells and NK cells.
A key step in Th2 differentiation is
the production of IL-4 by Mast cells
and eosinophil granulocytes then
later the T cells join to produce IL-4.
A key step in Th2 differentiation is
the production of IL-4 by Mast cells
and eosinophil granulocytes then
later the T cells join to produce IL-4.
The three types of effector T cell produce
distinct sets of effector molecules