Transcript Antigen

SPECIFIC CELLULAR
RESPONSE
Paulina Roszkowska
The lymphoid system
Main part - lymphocytes – differentiate from stem cells in the primary
organs, migrate to secondary, recognize antigens by specific receptors
• Central (primary) organs:
* thymus - proliferation and maturation T lymphocytes,
selection for tolerance to autoantigens
* bone marrow – proliferation and maturation B lymphocytes
• Secondary (peripheral): an environment in which
mature lymphocytes T i B interact with antigen, cooperate with
phagocytes and accessory cells
* spleen – responds to blood-borne antigens
* lymph nodes – lymph-borne antigens absorbed via skin,
* mucosal tissue - MALT (GALT, BALT), .. – protects the mucosal
surface
-
there is continuous lymfocyte traffic - from the blood stream
into lymphoid tissues and back again
Non-specific and Specific Immunity:
Contrasts
Non-specific
Specific
(natural, native, innate)
(acquired, adaptive)
• system in place prior to
exposure to antigen
– can be enhanced after exposure
to antigen through effects of
cytokines
• lacks discrimination among
antigens
•
•
•
is induced by specific antigen
Is activated later than non-specific
has memory
– Learnt by experience
– Enhanced by second
exposure
• Is poorly effective without
innate immunity
The non-specific and specific immune systems interact with each other!
Antigen (Ag)
A substance that can induce a specific
immune response and react with the
products of it.
Epitope
– single determinant of antigen,
binds with paratope of antibody
Feature of antigens
• Immunogenicity – ability of recognition
of the antigen and production of cellular or
humoral response
• Antigenicity - ability of raction with
products of cellular or humoral response
• Specificity – reaction of antibody or
specific lymphocytes with epitope
Hapten
A substance that is non-immunogenic but
which can react with the products of a
specific immune response. Haptens are
small molecules which could never induce
an immune response by themselves but
they can when coupled to a carrier
molecule.
Haptens have the property of antigenicity
but not immunogenicity.
Superantigens
– proteins produced by pathogens, which are
not processed by antigen presenting cells but
can binds to variable region of β chain on
TCR of T cells and to MHC class II on antigen
presenting cells (APC) and activate Tcell
– Large numbers of activated T cells release
cytokines having pathological effects
Antigenic peptides must
normally be processed
in order to triger the TCR
recognition in
MHC groove.
It gives:
low frequency of antigenantigen specific cells
Superantigens
(e.g.staphyloccocal toxins)
are not processed but
bind directly to MHC II only.
It gives:
high frequency of antigenantigen specific cells:
polyclonal response
ANTIGEN + LYMPHOCYT =
IMMUNE RESPONSE
but
• different antigens
• react with different cells of immune
system
• and cause different response
CELLS OF IMMUNE SYSTEM
Leucocytes
Adaptive and innate immunity depends upon LEUCOCYTES
Innate immunity is mediated largely by GRANULOCYTES
Adaptive immunity mediated by LYMPHOCYTES
The growth, development and
activities of granulocytes and
lymphocytes are interconnected
and co-operative.
Lymphocyte subsets
CLP
T CELLS
B CELLS
Common
lymphoid
precursor
T
Th
Activate B cells
and macrophages
T HELPER CELLS
CTL
Kill virusinfected cells
CYTOTOXIC T
LYMPHOCYTES
B
PC
Produce antibodies
PLASMA CELLS
Lymphocytes
20-40% of whole leucocytes in blood, morphologically
different:
• T - 70%
-TCR receptor + CD 3
– Th 1, Th 2 – helper
» 50-55%
» CD4 – co-receptor for MHC-II, 95% small lymphocytes
– Tc – cytotoxic
» 20-25%
» CD8 - MHC-I – 50% small lymphocytes
– Ts – suppressor ? (CD8 but also CD4)
• B
- 10-20%
-CD19 CD20 CD21 +
-IgM, IgD, MHC-II receptors, only few
IgG,IgA,IgE expression
• NK
- (CD56, CD57)
- large granular
have
Lymphocytes
• express characteristic surface markers detected by monoclonal
antibodies- cluster of differentiation antigens CD (> 150 is
known now)
• Markers are responsible for phenotype and biological function:
– T – CD2- binds sheep blood cells
– CD3- signal tranduction
• release cytokines:
• Th1: Il-2, IFN , TNF
• Th2: Il-2, Il-4, Il-5, Il-6, Il-9 Il-10, Il-13
• possess receptors for:
•
•
•
•
•
•
cytokins,
MHC,
Fc (CD16, CD64),
C,
integryns (CD2 - LFA), selektyns (CD62 - E, L, P)
T or B actiovation releases additional expression of surface
markers, antigens
Lymphocyte antigen receptors
Lyc
B
T
T and B cells are essentially inactive until they
encounter antigen.
T and B cells express ANTIGEN RECEPTORS
The B cell antigen receptor is a membrane-bound antibody
SURFACE IMMUNOGLOBULIN
The T cell antigen receptor IS NOT membrane bound
antibody but a distinct molecule
T CELL ANTIGEN RECEPTOR
Each antigen receptor binds to a different antigen
What Does The B Cell
Immunoglobulin (Ig)
Receptor Recognize?
1. Proteins (conformational
determinants, denatured or
proteolyzed determinants)
2. Nucleic acids
3. Polysaccharides
4. Some lipids
5. Small chemicals (haptens)
Uniqueness of B Cells
• Express both immunoglobulin (Ig) and
class II MHC on cell surface
• Capable of producing antibody of
same specificity as that of its surface
Ig
AND
• Capable of functioning as an antigen
presenting cell
What Does the T Cell Receptor
(TCR) Recognize?
Only fragments of proteins (peptides) associated
with MHC molecules on surface of cells
•
•
•
Helper T cells (Th) recognize peptide associated with
MHC class II molecules
Cytotoxic T cells (Tc) recognize peptide associated
with MHC class I molecules
Every TCR on an individual T cell has one specificity
T cell receptor (TCR)
• The specificity for immune responses
resides in the T cell receptor (TCR)
• recognizes pathogen (antigen)-derived
peptides bound to major histocompatibility
complex (MHC) molecules expressed on
the surface of nucleated cells –APC
(antigen presenting cells).
Types of antigens:
• T –dependent antigen
– need recognition by both T and B lymphocytes to produce
antibodies,
– most antigens,
– mainly proteins,
– humoral and cellular response
• T-independent antigen
– recognition by B lymphocytes B,
– mainly polysaccharides: capsule of S.pneumoniae,
H.influenzae, N.miningitidis
– only antibodies are produced, no cellular response
Location of Pathogen Determines
Which T Cell Population Responds
• Cytosolic:
– cells harboring pathogens in the cytosol are
recognized and killed by cytotoxic T cells (Tc) that
express CD8
• Vesicular:
– cells are recognized by a subpopulation of helper
T cells (Th1) that express CD4, which enable the
infected cell to kill the pathogen
• Extracellular: subpopulation of helper T
cells (Th2) that express CD4
Location of Pathogen Determines
Which T Cell Population Responds
Intracellular
•
reside in two intracellular compartments:
– Cytosolic:
• viruses and some bacteria
• cytosol and nucleus connected via nuclear
pores
• cells harboring pathogens in the cytosol are
recognized and killed by cytotoxic T cells (Tc)
that express CD8
Extracellular
- site of most bacteria as:
-T-independent antigen
-T-dependent antigen
subpopulation of
helper T
cells (Th2) that express CD4
– Vesicular:
• some bacteria, some parasites
• membrane-bound entities (endoplasmic
reticulum, endosomes, lysosomes, Golgi
apparatus)
• cells are recognized by a subpopulation of
helper T cells (Th1) that express CD4, which
enable the infected cell to kill the pathogen
elicits antibody (humoral) response
- elicits
cell-mediated response
Exogenous Antigens
must be processed in order
to be recognised by T cells
T
Y
Soluble
native Ag
Cell surface
native Ag
Soluble
peptides
of Ag
Cell surface peptides of
Ag presented by cells that
express MHC antigens
Cell surface
peptides
of Ag
ANTIGEN
PROCESSING
No T cell
response
No T cell
response
No T cell
response
No T cell
response
T cell
response
IMMUNE RESPONSE
Leukocyte Migration and
Localization
• Bone marrow and thymus (primary
lymphoid tissues)
– produce B cells and T cells
• B cells and T cells recirculate through
spleen and lymph nodes (secondary
lymphoid tissues)
Lymphocyte Recirculation
• Antigen presenting cells (APC) pick up antigen and
migrate to secondary lymphoid tissues and interact
with T cells and B cells
• Secondary lymphoid tissues (lymph nodes, spleen)
main sites where lymphocytes encounter antigen
• Frequency of lymphocytes having a receptor specific
for a given antigen is low
Leukocyte Migration and Localization
Bone marrow
Macrophage
Thymus
T
T
B
B
cell
cell
cell
cell
T
cell
Naive
lymphocytes
Dendritic
cell
B
cell
Spleen and lymph nodes
Primed lymphocytes
T
B
cell
cell
APC
Tissues
Antigen Presenting
APC – Antigen Presenting Cells
• Heterogenic population:
– Langerhans cells – present to Th1
– B cells– present to Th2
– macrophages– phagocytes
• Role of APC:
– antigen processing (degradation into small
peptides),
– binding with MHC-II and
– presentation to T CD4
• All cells can present antigen to T CD8 posses MHC-I
SELF MHC RESTRICTION
• In order for a T cell to recognize and respond to
a foreign protein antigen, it must recognize the
MHC on the presenting cell as self MHC.
– Helper T cells recognize antigen in context of class II
self MHC.
– Cytolytic T cells recognize antigen in context of class I
self MHC.
• The process whereby T cells become restricted
to recognizing self MHC molecules occurs in the
thymus.
Class I MHC
Molecules
Class II MHC
Molecules
• expressed on surface of
all nucleated cells
• expressed on surface of
some nucleated cells,
mainly antigen presenting
cells (APC)
• recognized by TCR of
helper T cells
• CD4 binds to class II
MHC-peptide complex
• source of peptide is
vesicular compartment
• recognized by TCR of
cytotoxic T cells
• CD8 binds to class I
MHC-peptide complex
• source of peptide is
cytosolic compartment
Different cellular pathways for
association of peptide with MHC
class I and class II molecules
Class I MHC Pathway
Peptide is presented
by MHC-I to CD8
cytotoxic T cell
Plasma membrane
Peptide passes
with MHC from Golgi
body to surface
Viral protein is made
on cytoplasmic
ribosomes
Globular viral
protein - intact
rER
Peptide associates
with MHC-I complex
Proteasome
degrades
protein to
peptides
Peptide transporter
protein
moves
peptide into ER
Golgi body
Peptide with MHC
goes to Golgi body
MHC class I alpha
and beta proteins
are made on the rER
Class II MHC Pathway
Peptide MHC-II
complex is presented
to CD4 helper T cell
Endosome fuses with
plasma membrane
Immunodominant
peptide binds
to class II MHC
Golgi
body
Globular
protein
CD4 helper T cell
Endosome
Fusion of endosome
and exocytic vesicle
Endocytosis
Lysosome
Exocytic vesicle fuses
with endosome
releasing Ii from αβ dimer
Protein is processed to
peptides in endosome
or lysosome
Class II MHC
α
Synthesis
3 chains: α,β and Ii
β Ii
Endoplasmic reticulum
Immune response
Different cells cause different
response
Immunologic responce
T cells
+ antigen
B cells
+ antigen
humoral antigen
T-independent antigen
memory T cells
memory
effector T cells
-
Tc lymphocytes
Th
macrophages
NK lymphocytes
memory B cells
memory
effector B cells
-plasma cells
antybodies
HUMORAL RESPONSE
CELLULAR RESPONSE
•
Main phases of the immune
response:
induction phase
– recognition of antigen
•
central phase
– activation,
– clonal selection and prolipheration of T
and B lymphocytes
•
effector phase
– elimination of antigen mediated by
antibodies and effector cells
Cell medited specific response
Immune
response
phases:
1. INDUCTION
–
recognition of antigen by T lymphocyte,
2. central phase
–
3.
the main function of CD4 cell- regulation by cytokines
EFFECTOR
–
elimination of antigen, pathogen:
•
•
•
•
macrophages activation (Th1 - IFN)) – better destroing of
intracellular bacteria: mycobacteria, brucella, listeria
cytotoxicity – T CD8 (Th - Il-2 + APC - Il-12) cell-cell interaction
against whole cells: virus-infected, tumour, transplant cells..by
perforins, Fas ligand
ADCC- antibody dependent cell citytoxity –K cells, receptor Fc
(CD16), bind antigens conected with cell
LAK – Il-2 activated lymphocytes NK ? TcCD8, NK activated,
• viruses in cytosol,
MHC class I pathway,
Tc response
• extracellular bacteria,
MHC class II pathway,
Th2 response, Ab formation
• intracellular bacteria,
MHC class II pathway,
Th1 response
Th response
Naïve Th Cells Can
Differentiate Into Th1 or Th2
Cells
Naive Th cells
Short-term
Long term
Chronic
stimulation
stimulation
Th1
cell
Memory cells
IFNγ
IL-2
ThP
ThO
ThM
cell
cell
cell
Th2
cell
IL-2
IFNγ
IL-2
IL-4
IL-5
IL-10
IL-4
IL-5
IL-6
IL-10
IL-2
Counter regulation of Th cell subsets
IFN-
Th1
-
IL-10
-
Th2
Balanced response
Th1
-
IL-10
IFN-
Th2
Th2 Dominant
Th1
Th1 Dominant
-
Th2
Functions of Th1 and Th2 Cells
Th1
Th2
cell
cell
Inhibits production
IL-10
IFNγ
IL-4 IL-5
Activates
Activates
Macrophage
Mast cell
B cell
Eosinophil
Antibodies (including IgE)
Th 1 response
Th1
-Th cells are a subset of T cells that express a unique
antigen on their surface called CD4.
-A subpopulation of Th1 cells, is the primary defense
against intracellular pathogens (inside vesicles).
– Th1 cells recognize antigen from the pathogen that are
expressed on the surface of infected cells
– release cytokines that activate the infected cell.
– Once activated, the infected cell can then kill the pathogen.
– For example, Mycobacterium tuberculosis, infects macrophages
but is not killed because it blocks the fusion of lysosomes with
the endosomes. Th1 cells that recognize M. tuberculosis
antigens on the surface of an infected macrophage can secrete
cytokines that activate macrophages.
Helper (Th1) T Cells
lysosome
Macrophage
Macrophage
antigen
mycobacteria
Infected macrophage
Activated infected
macrophage
Th1
cell
Central Role of Macrophages in
Natural and Specific Immunity
• Involved in initial defense and antigen
presentation and have effector functions
Invading agent
Macrophage
Antigen presentation
Macrophage
Activated macrophage
Macrophage
Th
cell
Cytokines
Lymphokines
Cytokines
Anti-microbial functions
Anti-tumor functions
Tc response
Cytotoxic T lymphocytes (CTL)
• CTLs are a subset of T lymphocytes that
express a unique antigen on their surface
called CD8.
• These cells recognize antigens from the
pathogen that are displayed on the surface
of the infected cell and kill the cell.
• CTLs kill by cytotoity and inducing
apoptosis in the infected cell
Cytotoxic (Tc) T Cells
A
B
Cell expresses
viral antigens
C
Cytotoxic
T cell
Virus infects cell
Infected cell is killed by cytotoxic T cell
by activation of nucleases that cleave
host and viral DNA
Features of Tc Killing
• Antigen-specific
• Requires cell-cell contact
• Each Tc capable of killing many target
cells
Interactions of Tc Cell and Target Cel
T cytotoxic
lymphocyte
LFA-1
TCR
CD8
peptide
Target
cell
ICAM-1
LFA-2
Class I
MHC
LFA-3
Mechanism of Arming Tc Cells
Class I
MHC
1. Cell expressing class I MHC
presents antigen ( )
to a pre-Tc cell
3. Th cell
makes cytokines
Pre-Tc cell
IFN
IL-2
2. Antigen-presenting
cell presents antigen in
association with
class II MHC to Th cell
T helper cell
Class II MHC
APC
4. Pre-Tc cell
differentiates to
functional Tc cell
Tc cell
5. Tc recognizes antigen on
class I MHC-expressing target cell
6. Target cell
is killed
Main Mechanism of Tc Killing
• Tc granules contain: perforin and granzymes
• Upon contact with target cell, granule contents
released,
– perforin polymerizes and forms channel in target
cell membrane
– Granzymes (serine proteases) enter target cell
through channel, activate caspases and
nucleases, lead to apoptosis of target cell
Mechanism of Tc Killing
Tc cell
Perforin
Ca++
polymerizes
Perforin
monomers
Tc cell
Polyperforin channels
Target cell
Target cell
Granzymes
Which cells are involved in cellular
immune response?
Lymphokine activated killers (LAK)
- develope from NK influenced by IL 2
- perform their function by antibody
dependent cytotoxicity (ADCC) which
requires an interaction with humoral
specific response
Mediators and Regulators of
Specific Immunity
•
•
•
•
•
Interleukin-2 (IL-2)
Interleukin-4 (IL-4)
Interleukin-5 (IL-5)
Interleukin-10 (IL-10)
Interferon-gamma (IFN-γ)
Interleukin-2 (IL-2)
• Produced by Th>>Tc
• Main growth factor for T cells
T cell
B cell
Monocyte
Activation
IL-2
secretion
NK
Stimulation
of division
T cell
Stimulation
of division and IFN gamma
release (and other
Increase in NK
mediators)
Cell activity
Interleukin-4 (IL-4)
• Produced by Th2 cells
• Stimulates Ig class switching to IgE
isotype
• Stimulates development of Th2
cells from naïve Th cells
• Promotes growth of differentiated
Th2 cells
Interleukin-5 (IL-5)
• Produced by Th2 cells
• Promotes growth and differentiation
of eosinophils
• Activates mature eosinophils
• IL-4 and IL-5 can work together
Helminths opsonized with IgE can be
killed by activated eosinophils
Interleukin-10 (IL-10)
• Produced by activated macrophages,
Th2 cells
• Inhibits production of IFN-γ by Th1
cells needed to activate macrophages
Interferon-gamma (IFN-γ)
• Produced by Th cells >> Tc and NK cells
• Numerous functions in both natural and specific
immunity
Th1 cell >
Tc cell
NK
Granulocyte
Endothelial cell
Activation
Activation
IFN gamma
secretion
Macrophage
NK
Activation
Many cell types
Weak anti-viral activity,
Stops cell division,
Stops hematopoiesis
T cell
T cell activation
B
cell
Increase in
NK
cell activity
Many cell types
Differentiation, Induction of class I
Stops cell division and class II MHC
THE END