You are on page 1of 37

Specific Immune Response

The key cells involved in the specific immunological response are


LYMPHOCYTES, falling into 2 main groups:

1. B Cells responsible for antibody (Ab) production


2. T Cells important in the Induction Phase and responsible for
cell-mediated response

In the specific immune response there are 2 main phases:

1. Induction Phase
1a.Recognition of antigen ⇒ response initiation
1b.Development and amplification
2. Effector phase -------- eliminates invader
This is further subdivided into:
2a. Humoral Component (Antibody-mediated) B cells
2b. Cell-mediated Component T cells
Specific Immune Response
Specific Immune Response

Induction Phase

This involves the activation of T cells and B


cells when a foreign antigen (Ag) is
presented to a naïve Helper T Cell by an
Antigen Presenting Cell (APC).
Specific Immune Response
Induction Phase

Antigens reach the local lymph nodes via the lymphatics.


The antigen is presented to lymphocytes by Antigen Presenting Cells.
The APC’s ingest and process the Ag and present it to an uncommitted or
naive CD4-positive Helper T cell in conjunction with the MHC.

These naive Helper T Cells begin to produce Interleukin-2-receptors as well as


generating Interleukin-2.

Interleukin-2 is a cytokine that has an autocrine function, that is, it causes the
proliferation of activated Helper T Cells which are now called Th0 cells.

Th0 cells then produce either Th1 or Th2 cells

Th2 cell production is stimulated by IL-4 (Interleukin-4) from Th0 cells.

Th1 cell production is stimulated by IL-12 (Interleukin-12) secreted from the


APC’s after binding to Helper T cells.
Specific Immune Response

Figure 20-10 Vander et al, 8th Ed.


Specific Immune Response
These naïve Helper T Cells begin to
produce Interleukin-2-receptors as well
as generating Interleukin-2.

Interleukin-2 is a cytokine that has an


autocrine function, that is, it causes
the proliferation of activated Helper
T Cells which are now called Th0
cells.
Th0 cells then produce either Th1 or
Th2 cells

Th1 cell production is stimulated by


IK-12 (Interleukin-12) secreted from
the APC’s after binding to Helper T
cells.
Th2 cell production is stimulated
by IL-4 (Interleukin-4) from Th0
cells.
Specific Immune Response
Induction Phase

Th2 cells under the influence of IL-4 will


promote the proliferation of B Cells
which are responsible for our Antibody
mediated immune responses.

Some B Cells become:

Plasma Cells and release Ab into blood.


Memory B Cells that retain the blueprint
of the Ag for future Ab production
should the same Ag enter the body later.
Specific Immune Response
Induction Phase
Th1 cells produce several cytokines but
mφ activating cytokines and Interferon γ
are most important initially.

Interferon g is responsible for stimulating


CD8 T Cells to become Cytotoxic T Cells

This is the beginning of the cell-mediated


pathway of the immune response.
Specific Immune Response
Specific Immune Response
Specific Immune Response
Induction Phase Summary

The 2 subsets of T Cells are important because they are responsible for
providing the balance in response by the immune system.

Also any dysfunction at this level will lead to deficiencies in both Ab-mediated
and/or cell-mediated immunity.

Th1 Cells and Cell-Mediated Immunity


Th1Cells produce the cytokines (IL-2, TNF-β and IFN γ) that:
• activate macrophages
• stimulate CD8+ lymphocytes to release IL-2 yielding cytotoxic T cells
•inhibit Th2 cells by INFγ action.

Th2 Cells and Ab-Mediated Immunity


Produce cytokines (IL-4, TGF-b, IL-10) that:
• Stimulate B Cell proliferation (CD4+ Cells)
• Stimulate differentiation of eosinophils
• Inhibit Th1 Cell function.
Ag
APC
Ag Processing
B Ab
CD8 1. 2.

Help
Help

CD4
The central event in the generation of both
humoral and cell-mediated immune responses
is the activation and clonal expansion of TH
cells.
Activation of TC cells is generally similar to TH
cell activation.
TH cell activation is initiated by interaction of
the TCR-CD3 complex with a processed
antigenic peptide bound to a class II MHC
molecule on the surface of an antigen-
presenting cell.
The T cell Receptor
• Similar in structure to Immunoglobulins (similar to a single Fab
fragment.
• Composed of two glycoprotein chains (α /β or γ /δ ). Most
mature T cells have TCRs composed of an α chain and a β chain
(they are called α /β T cells).
• Each chain has a constant region and a variable region, similar to
an antibody light chain. Epitope-binding site

• A TCR recognizes a small α chain β chain


(8-13 aa) peptide epitope Variable region
displayed on MHC
Constant region

Transmembrane region
TCR compared to Immunoglobulins
Similarities
• Both have specific Antigen-binding region created by the variable regions of two
polypeptide chains.
• Both display great potential for diversity via genetic recombination at the
genome level
Differences
• A TCR is monovalent (has one binding site). An Ig is bivalent (has two binding
sites).
• The TCR has no secreted form. It is always membrane-bound.
• The TCR does not recognize free antigen. Antigen must be presented to a T cell
on an MHC molecule (next week).
• There is no class switching for the TCR. Once made, the TCR does not change.
Epitope-binding site
α chain β chain
Variable region

Constant region

Transmembrane region

T cell Receptor Immunoglobulin


α TcR β
TcR-CD3 complex
CD3 CD3
ε δ γ ε
The intracytoplasmic region
of the TcR chain is too short
to transduce a signal
− − +
+ + − −
The CD3γ , δ , ε or ζ (zeta) chains
are required for cell surface
expression of the TcR-CD3
complex and signalling
through the TcR

ζ ζ

Signalling is initiated by aggregation of TcR by MHC-peptide complexes on APC


The activation of T-cells requires
two signals
• Signal 1, the initial signal, is generated by
interaction of an antigenic peptide with the
TCR-CD3 complex.
• signal 2, A subsequent antigen-nonspecific
co-stimulatory signal, is provided primarily
by interactions between CD28 on the T cell
and members of the B7 family on the APC.
Both antigen-specific (signal 1) and co-stimulatory signals
(signal 2) are required for T cell activation
Signal 2: B7 on activated dendritic cell binds to CD28 on T cells

2
B7 is the ligand
CD28 is the receptor

There are two alleles of B7


B7.1 = CD80
B7.2 = CD86
Signal 2 alone has no effect on the T cell
Signal 1 alone inactivates the T cell
• Th cell activation:
• Signal 1 ( binding of the lymphocyte to
antigen via its TCR);
• Signal 2 (through engagement of co-
stimulatory molecules CD28 binding to
B7).
• Full activation requires these two
signals.
• Tc cell activation:
• Signal 1 (binding of the lymphocyte to
antigen via its TCR);
• Signal 2
– co-stimulatory molecules supplied by
APCs that have been conditioned by Th
cells.
– cytikines produced by Th cells and APCs
• The affinity of T-cell receptors for peptide-
MHC complexes is weak compared with
antigen-antibody interactions
• T-cell interactions do not depend solely on
binding by the TCR;
• cell-adhesion molecules strengthen the
bond between a T cell and an antigen-
presenting cell or a target cell.
• Several accessory membrane molecules,
including CD2, LFA-1, CD28, and CD45R
bind independently to other ligands on
antigen-presenting cells or target cells .
• Binding of the coreceptors CD4 and CD8
and the other accessory molecules to their
ligands strengthens the bond between the
interacting cells and/or facilitates the
signal transduction that leads to activation
of the T cell.
• Once cell-to-cell contact has been made
by the adhesion molecules, the T-cell
receptor may scan the membrane for
peptide-MHC complexes.
Both trafficking and initial interactions of T cells with APC
requires adhesion molecules
• Interaction of a TH cell with antigen initiates
a cascade of biochemical events that induces
the resting TH cell to enter the cell cycle,
proliferating and differentiating into
memory cells or effector cells.
• Many of the gene products that appear upon
interaction with antigen can be grouped into
one of three categories depending on how
early they can be detected after antigen
recognition.
T cell help to B cells - B cells are co-stimulated

Signal 1 antigen & antigen ACTIVATION


receptor

B
YYY Th
Signal 2 - T cell help

CD40 T cell antigen receptor


Co-receptor (CD4)
MHC class II
CD40 Ligand (CD154)
and peptide
Antigen presentation - T cells are co-stimulated
Signal 1 antigen & antigen
receptor

APC Th ACTIVATION

Signal 2

B7 family members (CD80 & CD86) CD28

Costimulatory molecules are expressed by most APC including dendritic cells,


monocytes, macrophages, B cells etc., but not by cells that have no
immunoregulatory functions such as muscle, nerves, hepatocytes, epithelial cells etc.
IL-2 is key to antigen-induced T cell
proliferation and differentiation

Autocrine stimulation
(it makes a hormone that
is secreted and stimulate
the cell that made it

Cells divide 2-3


times per day for 4
or 5 day
(212 = 4096)

IL-2 used to be
called “T cell
growth factor”
Specific Immune Response
Effector Phase

Antibody-Mediated (Humoral) Response

Abs are immunoglobulins (Ig’s) that have 2 functions:

1. Recognize and interact specifically with foreign Ag’s.


2. Activate one of more host defence mechanisms.

Structure of Antibodies

Y - shaped proteins containing:

Fab portion that has the


recognition site for Ag

Fc portion that activates


host defences.
Specific Immune Response
Effector Phase

Among B cells there are clones that express individual Ab’s to recognize
specific Ag’s.

Remember 5 classes of Ig’s: IgA, IgD, IgE, IgG and IgM

Ab’s improve the host’s ability to recover from an invading Ag associated with
a virus or a bacterial toxin.

Ab’s interact with elements of the innate immune system as follows:

• Activate Complement
• Stimulate Ingestion of Bacteria
• Assist Cytotoxic Cell Function
• Stimulate Allergic Reactions
Specific Immune Response
Ab and Complement

Ab binds to Ag forming an Ag-Ab Complex.


This exposes the Fc portion of the Ab which is a binding site for Complement.
Complement-Fc Complex results in activation of the complement sequence,
particularly the Classical Pathway.

Ie. C3a anaphylatoxin


C5a chemotaxic factor
C3b opsonin

Leading to lysis of the invading cell.

Ab and Ingestion of Bacteria

Ag-Ab Complex, exposes Fc portion


Attracts phagocytic cells (neutrophils and macrophages)
Begins ingestion process.
Specific Immune Response
Effector Phase

Ab and Cellular Toxicity


Ag-Ab Complex allows cross-links between a parasite and eosinophils.
Eosinophils kill the microorganism.
Useful for large pathogens such as protozoa and worms.

Ab and Allergic Reactions

Mast Cells and Basophils have receptors for IgE which can become attached
to the cell membrane.

When Ag reacts with this cell-fixed Ab it yields an enormous response with the
release of many inflammatory mediators.
Specific Immune Response
Effector Phase

Cell-Mediated Response
Lymphocytes involved are both:

• CD8+ (Cytotoxic T Cells) and


• Inflammatory, cytokine releasing Th1 Cells (CD4+)

Cytotoxic T Cells

Attack virus-infected tissue cells in 2 steps:

1. Recognition and signalling that the cell is infected.


Expression on the cell surface of peptides derived from the pathogen
in association with MHC protein.

2. Protein-MHC complex is recognized by CD8+ T Cells which destroy


virus-infected tissue cell.
Specific Immune Response
Effector Phase

Cytokine-Releasing Th1 Cells (CD4)

Their main role is to activate macrophages.


Some pathogens have evolved a survival mechanism of multiplying inside
macrophages after being ingested.
E.g. Mycobacteria and Listeria

An infected Macrophage produces an Ag-MHC complex on its own surface


which is recognized by cytokine-releasing Th1 cells. The cytokines released by
the Th1 cells help the macrophage to kill the pathogen inside it.

In all other cases, Th1 cells activate macrophages to engulf, ingest and
digest the invading pathogen.

In the process an Ag is bound to MHC to present Ag to the T Cells.

What happens next depends on whether Th1 or Th2 cells are stimulated.