Transcript 4. immune_team_

Immune team
Cell Mediated Immunity
(CMI)
Cell-Mediated Immunity (CMI)
Antigen
T-lymphocytes
Immune responses
Cell Mediated Immunity
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Cell-mediated immunity (CMI).
Remember :CD4 ( T helper ) is attracted to MHC II
CD8 ( T cytotoxic ) is attracted to MHC I
• T cells (lymphocytes) bind to the surface of
other cells (Antigen Presenting Cells) that
display the antigen and trigger a response
Antigen Presenting cells that has MHC II
Monocytes : Peripheral blood
Macrophages : Tissues
Dendritic cells : Lymphoid tissues
Langerhans cells : Epidermis
B-cells : Lymphoid tissue, Blood
Lymphocyte
Macrophage
Lymphocyte
Cell Mediated Immunity
The T helper cell need the help from ( antigen presenting cell ) to
recognize an antigen and produce an effect against that antigen
The APC ( antigen presenting cell ) hold the foregin antigen in one
hand , and hold its MHC class in the other hand
Then it present both his MHC class and the foregin antigen to T
helper cell in the same time
So T helper cell first recognize by MHC II that this is a normal body
cell , then it recognize by the antigen that there is a foregin antigen
having fun
in the body that need to be killed so it produce a
response against it
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2
5
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Invariant chain(Ii)
In The Previous Picture
In ( 1 ) you can see a foreign body in red color havind a dark black part
called the most antigenic part and that what stimulate T cells
In ( 2 ) the foreign body get endocytosed into an endosome
In ( 3 ) the endosome then fuse with the lysosome to degrade the antigen
into small parts to separate the most antigenic part from the rest of it
In ( 4 ) the ER produce the MHC in vesicles that fuse with the endosome
In ( 5 ) the MHC work as a hand that hold the most antigenic part and
present it to the T cell
In ( 6 ) the MHC and most antigenic part go to the surface of the cell and
do the presentation to T cell
[ this process happen in both MHC class I and II cells ]
T cell Activation
Antigen Presentation
T cell Activation Antigen Presentation
CD4 ( T helper ) is the
brain of the immune
system
All effector cells work
under its command
HI
CMI
T lymphocytes
Other cells
If the
antigen
wes
intracellular the (
CMI ) will
work , but
if the
antigen
wes
extracellular the (
HI ) work
In viral infections like ( HIV ) , because the virus will inter the
cell and force it to produce endogenous proteins for the virus so
the foreign protein ( antigen ) come from inside the cell and
that’s way it is called endogenous
1. Endogenous antigen
2. Exogenous antigen
Like microbes
Virus
Target cell
Target cell
The virus can not make its own proteins ( antigens ) so it need a host
cell to produce its proteins ( endogenous antigens ) , the endogenous
antigen will bind with ( MHC I ) of the effected cell and appear on
the surface to be recognized by CD8 ( T cytotoxic ) to kill it
Target cell
Target cell
Host cell
Transcription
Translation
Viral protein
Type of antigen
Type of MHC
Type of T cell
Exogenous
MHC II
CD4
Endogenous
MHC I
CD8
Exogenous antigen like
Microbes
Proteins
Cell-mediated immunity
Exogenous antigen
CD4+ T-lymphocytes
(CD4+ cells)
Class II MHC
APC
APC
Antigen presenting cells
Monocytes/Macrophages
Dendritic cells
Langerhans cells
B-cells
CMI
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4
2
3
Invariant chain(Ii)
TCR-MHC interaction
T cells
T cells
TCR
T cells
TCR
X
MHC
APC
TCR
X
MHC
APC
Recognition
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Y
MHC
APC
No Recognition
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3
In the previous figure
( there is an interaction between T cell receptor and MHC )
In ( 1 ) the MHC class is the right class for that T cell receptor and the
picked up part of the foreign antigen is the most antigenic part , so there
will be recognition and response to that antigen
In ( 2 ) the picked up part of the antigen is the most antigenic part , but
the MHC class is not right for that T cell receptor , so there will not be a
recognition and of course no response
In ( 3 ) the MHC class is right for that T cell receptor , but the picked up
part of the antigen is not the most antigenic part , so no recognition and
no response
So to have a recognition and response to an antigen by effected cells you
need ( the right type of MHC , the right part of antigen ) to the TCR
CD4-MHC class II interaction
Antigen presenting cell
CD4
MHC
class
II
Antigen presenting cell
CD4
Antigen presenting cell
CD4
TCR
T cell
T cell
T cell
Cell-Mediated Immunity
• Lymphocytes: (B & T lymphocytes)
• B lymphocytes ("B cells"): These are responsible for
making antibodies (humoral immunity)
• T lymphocytes ("T cells"): CMI
• Subsets include:
– CD8+ cytotoxic T lymphocytes (CTLs) that kill virus-infected
and tumor cells
– CD4+ helper T cells enhance CMI and production of antibodies
by B cells
Cell-Mediated Immunity
• Examples of Cell-Mediated Immunity
• Delayed-Type Hypersensitivity (DTH): the tuberculin
test (or Mantoux test)
• Tuberculosis: a chronic disease, caused by
Mycobacterium tuberculosis
• The response to tuberculin is called "delayed" because
cells take long time to arrive to site of infection
• in contrast to the "immediate" responses characteristic of
many antibody-mediated sensitivities like an ( allergic
response to a bee sting)
• So immediate hypersensitivity is mediated by humoral
immunity , but delayed hypersensitivity and chronic
diseases is mediated by cell mediated immunity
Cell Mediated Immunity
• DTH is a cell-mediated response
• Anti-tuberculin antibodies are rarely found
in tuberculin-positive people
• The T cells responsible for DTH are
members of the CD4+ subset
Cell-Mediated Immunity
• Contact Sensitivity
• Many people develop rashes on their skin following
contact with certain chemicals such as nickel, certain dyes,
and the active ingredient of the poison ivy plant
• The response takes some 24 hours to occur, and like DTH,
is triggered by CD4+ T cells
• The actual antigen is probably created by the binding of
the chemical to proteins in the skin
• The fragments of antigen are then presented to CD4+ T
cells by phagocytic cells in the skin by antigen presentation
Activation of helper T cells
• Requires recognition of MHC - antigen complex
on the surface of antigen-presenting cells eg,
macrophages consisting of both antigen and class
II MHC proteins
• Viral antigens are recognized in association with
class I MHC proteins
• The activation of T cell in general by interaction
between MHC – antigen complex and T cell
receptor is called MHC restriction
Cellular Basis of Immune Response
• To activate T helper cell and initiate a response
you need two signals ( 2 interactions )
• First signal
• Interaction between ( Class II MHC + antigen )
with TCR
• ] mediated by IL-1, LFA-1 with ICAM ( InterCellular Adhesion Molecule 1) [
• Second signal (Co - stimulatory signal)
Interaction between B7 on APC with CD28 on T
lymphocyte
The two reactions must happen to initiate the
immune response
T helper cell
CD28
TCR
antigen
B7
MHC
APC
T cell Activation
• In the absence of co-stimulatory signal , state of
unresponsiveness called “anergy” develops
• Production of co-stimulatory protein depends on
activation of the toll like receptor on antigen
presenting cell
• Foreign antigens such as bacterial proteins induce
B7 protein where as self proteins do not
T cell Activation
• After antigen recognition by TCR, signal is
transmitted through CD3 molecule (
receptor )
• This results in influx of calcium into the cell
• Calcium activates calcineurin
• Calcineurin activates gene for IL-2 and its
receptor
Out come of T helper cell activation
• Production of IL-2 and its receptor
– IL-2 is also know as T cell growth factor
– Proliferation of antigen specific T cells
– Effector and regulatory cells are produced
along with “memory” cells
– IL-2 also stimulates CD8 cytotoxic cells
Retain memory for
different
pathogens and
proliferate in later
exposure to that
pathogen
T helper cell
Proliferate
into
memory
effector
Produce
cytokines and
activate other
cells
Out come of T helper cell activation
• Production of Gamma Interferon (IF)
( IF is an antiviral substance that will kill cell infected
by viruses and will make the cells resistant to viruses
so virus can not enter to cells , ( used in hepatitis )
– It increases expression of Class II MHC proteins
– It enhances the ability of APC to present antigen to
T cells
– It enhances the microbicidal activity of macrophages
– Enhances immune response
Out come of T helper cell activation
• Memory T cells
• Respond rapidly for many years after initial
exposure to antigen
• A large number of memory cells are produced so
that the secondary response is greater than the
primary
• Memory cells live for many years and have the
capacity to multiply
• They are activated by smaller amount of
antigen
• They produce greater amounts of interleukins
Effector functions of T cells
1. Delayed type of hypersensitivity mediated by
Th-1 type of CD4 positive cells
2. Cytotoxicity: mediated by CD8 +ve cells.
Directed against virus infected cells, tumor
cells and allografts
Killing by cytotoxic cells
– Perforins ( a chemical makes wholes in cell
membrane
– Granzymes – degrading enzymes
– Fas-Fas Ligand interaction - apoptosis
– Antibody dependent cellular cytotoxicity
– Immune surveillance
– Allograft rejection
The mechanism by which CD8 cell deal with cells
that have strange antigen on their surface is :-
1- secrete perforin which is a peptide that’s make wholes in
cell membrane
2- secrete enzymes which lyse the cell membrane
3- secrete cytokines like ( TNF ) which destroy cell
membrane
Killing Mechanisms of Cytotoxic
T cells
perforin
enzymes
cytokines
Activation of B cells
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B cell functions as APC
Multivalent antigen binds to surface IgM
Cross links adjacent Ig molecules
Igs aggregate to form “patches” and migrate to
one pole to form a cap
• Capped material is endocytosed
• Antigen is processed and epitopes appear on the
cell surface in association with Class II MHC
proteins