Download for T cell activation A

IMMUNOLOGY
7105306
Part-9
Capture of Microbes by Antigen-Presenting Cells
and
Cell-Mediated Immune Responses
References:
Immunology , David Male et al 8th ed 2013
Basic Immunology , Abul K. Abbas and Andrew H. Lichtman, 3ed, 2011
Instructor: Dr Alaeddin Abuzant, PhD Microbiology and Immunology
Email: [email protected]
Microbes usually enter the body through the skin, the gastrointestinal tract (by ingestion),
and the respiratory tract (by inhalation). (Some insect-borne microbes may be injected into
the bloodstream as a result of insect bites.)
All of the interfaces between the body and the external environment are lined by continuous
epithelia.
The epithelia and subepithelial tissues contain a network of dendritic cells(the same cells are
present in the T cell zones areas of peripheral lymphoid organs) .
These dendritic cells, are phagocytic cells. They belong to innate immune cells and play a
major role in linking innate to adaptive immune response
In the skin, the epidermal dendritic cells are called Langerhans cells.
.
Epithelial dendritic cells are said to be “immature,” . However, they are vey good in
phagocytosis of microbes and damages cells
They are called immature because they are inefficient YET to stimulate T lymphocytes
activation
The immature dendritic cells express membrane receptors (Pattern recognition receptors(
PRR) by which that recognize microbes and damaged cells .
Dendritic Cell Activation:
Microbes can activate dendritic cells by binding to PRR such as Toll-like receptors (TLRs)
by generating activating signals using their cytoplasmic ITIM motifs.
PRR such as TLR receptors are also found on resident macrophages found in tissue.
These microbes can detected by macrophage Toll like receptors leading for phagocytosis
and production of inflammatory cytokine s such tumor necrosis factor (TNF) and
interleukin-1 (IL-1). They cytokines can also activate near by Denritic cells
So, dendritic cells can be activated by: by their TLR signaling and by inflammatory
cytokines released by local macrophages at infection site
Activation of Dendritic cells results several changes in their phenotype and function.
Activated Dendritic Cells:
They become more rounded ( lose their dendrites)
Become less phagocytic and lose their adhesiveness for epithelia and begin to express
CCR7 chemokine receptor that is specific for chemo attracting cytokines (chemokines)
produced in the T cell zones of lymph nodes. These chemokines direct the dendritic cells to
exit the epithelium and migrate through lymphatic vessels to the lymph nodes draining that
epithelium
During the process of migration, the dendritic cells mature from cells designed to capture
microbes into APCs that are capable of activating T lymphocytes.
This maturation of dendritic cells is reflected in:
1- Increased synthesis and stable expression of MHC molecules, which display antigen
to T cells,
2- Expression of co-stimulatory molecules that are required for full T cell responses (B
& needed for the second signals)
3- Production of cytokines that play role in T cell differentiation
Notes:
Soluble microbial antigens in the lymph are picked up by dendritic cells that reside
in the lymph nodes
Blood-borne microbes and microbial antigens are handled in essentially the same
way by dendritic cells in the spleen.
Recall that naive T lymphocytes continuously re-circulate through lymph nodes
and also express CCR7 chemokine receptor , which promotes their entry into the T
cell zones of lymph nodes in response to chemokines released from T cells zones.
Therefore, dendritic cells bearing captured microbes or microbial antigen and
naive T cells come together in lymph nodes.
This process is remarkably efficient; it is estimated that if microbes or microbial
antigens are introduced at any site in the body, a T cell response to these antigens
begins in the lymph nodes draining that site within 12 to 18 hours ( or at MALT).
***The capture and presentation of protein antigens by dendritic cells.
Immunol Lett. 2006 Apr 15;104(1-2)
Expression and role of Fc- and complement-receptors on human dendritic cells.
Bajtay Z1, Csomor E, Sándor N, Erdei A.
Abstract
Dendritic cells (DCs) are professional antigen presenting cells, which take up
pathogens/foreign structures in peripheral tissues, then migrate to secondary lymphoid
organs where they initiate adaptive immune responses by activating naive T-cells. In the
early phase of antigen uptake pattern recognition receptors (including mannose-,
scavenger- and toll-like receptors) that recognize pathogen-associated molecular patterns
play an important role. Later receptors binding opsonized antigen are also involved in
phagocytosis. These cell membrane molecules include various Fc-receptors, recognizing
different isotypes of antibodies and various complement-receptors, such as CR3, CR4 and
the C1q-binding complex of calreticulin and CD91.
Different types of APCs Serve distinct functions in T cell–
dependent immune responses.
The type of activated dendritic cells influence the nature of T cell differentiation (
mainly CD4 T cells)
Various subsets of dendritic cells can direct the differentiation of naïve CD4+ T cells
into distinct populations ( TH1, TH2, Th17 and regulatory CD4 T cells) that function in
defense against different types of microbes .
 Differention of CD4 T cells into different types of effector CD4 T cells is mediated by
the cytokines they were exposed to during the activation process
Cross-Presentation initiating the responses of CD8+ T
lymphocytes to the antigens of intracellular microbes
The immune system, and especially CD8+ T lymphocytes, must be able to recognize
and respond to the antigens of these intracellular microbes.
However, viruses may infect any type of host cells. These infected cells may not
produce all of the signals that are needed to initiate T cell activation.
How, then, are naive CD8+ T lymphocytes able to respond to the intracellular
microbes?
A likely mechanism is that dendritic cells ingest infected cells and display the antigens
present in the infected cells for recognition by CD8+ T lymphocytes
This process is called cross-presentation (or cross-priming), to indicate that one
cell type, the dendritic cells, can present the antigens of other cells, the infected cells,
and prime (or activate) naive T lymphocytes specific for these antigens.
The dendritic cells that ingest infected cells may also present microbial antigens to CD4+
helper T lymphocytes.
Thus, both classes of T lymphocytes, CD4+ and CD8+ cells, specific for the same microbe
are activated close to one another.
This process may be important for the antigen-stimulated differentiation of naive CD8+
T cells to effector CTLs, which in some cases require help from effector CD4+ cells.
Part-II
Cell-Mediated Immune Responses
There are two types of intracellular infections during which microbes survive within
cells: and require cell mediated immunity:
First: microbes are ingested by phagocytes as part of the early defense
mechanisms of innate immunity, but some of these microbes have evolved to resist the
microbicidal activities of phagocytes and instead of being killed, these microbes survive and
replicate within the phagocytes.
Second: viruses bind to receptors on a wide variety of cells and are able to infect and
replicate in the cytoplasm of these cells. These cells often do not possess intrinsic
mechanisms for destroying the viruses.
( Recall that cells infected with viruses produce alpha interferones as a very early defense
step against viral infection. Alpha interferones may interfere with viral replication, however,
they do not always succeed)
The arm of the adaptive immune response whose role is to combat/fight infections by
intracellular microbes is represented by T lymphocytes, and is known as cell mediated
adaptive immune response that include CD4 and CD8 T cells.
Recall that, CD4+ helper T lymphocytes also help B cells to produce antibodies. Although
antibodies are important when dealing with extracellular microbes or toxins, some times
antibodies play an important role in destroying infected cells by the process (ADCC)
mediated by NK cells and macrophages
Activation of T lymphocytes:
Activation of Naive T cells involves three major steps:
1. Recognition of major histocompatibility complex (MHC)- displaying microbial peptide
antigens on antigen-presenting cells (DCs)
2. Recognition of co-stimulatory molecules on DCs( B7)
3. Exposure to cytokines ( these cytokines are produced by DC, other cells, or by
activated T cells them selves)
( T cell activation requires several TCR engaged to several MHC. This lead to receptor
aggregation that is important for triggering of activation signals . Activation signals are
triggered by TCR complex, CD co-receptor, and CD28)
Triggering of activation signals result in the following events in Naïve T cells:
1- Activation of surface adhesion molecules( integrines) that increase binding of naïve
T cells to DCs ( this is important for T cell activation)
2- Expression of CD40 Ligand, which binds to CD40 on DC ( this will enhance the
activation process by increasing the expression of B-7 on DC. This will increase the
second signal triggered by CD28 molecules expressed on T cells)
3- Production cytokines, such as IL-2 as well as completing the expression of IL-2
receptor on the T cells being activated
This leads to an autocrine effect of IL-2 that results in proliferation of activated T
cells (clonal expansion)
4- Differentiate of activated T cells into:
1. Effector cells, which serve various functions in cell-mediated immunity
2. Memory cells, which survive for long periods.
Phases of T Cell Activation
Antigen Recognition by naïve T cells , Co-stimulation of T cell b y B-7, and
Exposure to cytokines results in the following:
1. The TCR recognizes MHC-associated peptide antigens---activation signal 1
2. CD4 or CD8 co-receptors recognize the MHC molecules---activation signal 1
3. Signal 1 causes activation of adhesion molecules LFA-1 that strengthen the
binding of T cells to DCs ( activated LFA-1on T cells binds to ICAM-1 on DCs)
(Note: activation of LFA-1 on T cells is triggered by signals from TCR or a chemokine
receptor)
1. Receptors for co-stimulators such as CD28 on T cells recognize co-stimulatory
molecules on activated DCs ( B7-1 and B7-2). This causes CD28 to trigger the
signal 2 needed for T cell activation ----activation signal 2
5. First and second signals induce expression of CD40 ligand (CD40L) on T cells being
activated. CD40 L binds to CD40 on DCs ( this will enhance the activation process by
increasing the expression of B-7 on DC----Increase the second signal triggered by
CD28 as more and more CD28 on T cells being activated bind to B 7 on DCs
(Amplification of the second signal)
6. The first signal with amplified second signal induce the production of IL-2 by T cells
being activated. In addition, these signals will induce the completion of IL-2
receptor on the T cells being activated . (IL-2 produced by T cells being activated
binds to the completed IL-2 receptor on the same cells to exert an autocrine effect
that triggers T cell proliferation (clonal expansion)
7. Exposure of activate T cells to cytokines from DCs ( or other cells) play a major role
in T cell differentiation into effector T cells and memory T cells
IMPORTANT NOTE:
CD4 +T cells differentiation into TH1 Th2 Th17, Th19 and regulatory CD4 T cells is
determined by the types of cytokines they are exposed to during the activation process
/which can also be determined by the type of DC
Accessory Molecules of T lymphocytes Involved
in the Activation Process
The molecules other than antigen receptors that are involved in T cell responses to
antigens are called accessory molecules of T lymphocytes
Accessory molecules are invariant ( conserved) among all T cells. Their functions fall
into two categories:
1- Signaling molecules such as CD3 and ζ chain CD4/CD8 (first signal) and CD28 (
second signal)
2- Adhesion integrins such as LFA-1
T cell Activation:
Two or more TCR complexes together with their co-receptors are needed to be
engaged simultaneously with several MHC (harbor foreign peptide) to initiate the T
cell response.
This is because only when multiple TCRs and co-receptors are brought together an
appropriate biochemical signaling cascades is triggered
In addition, each T cell needs to engage antigen (i.e., MHC-peptide complexes) for a
long period, at least for several minutes, or multiple times to generate enough
biochemical signals to initiate a response. This can be mediated by adhesion
molecules on T cells such as LFA-1 that bind to ICAM-1 on DC. On Naïve T cells, LFA-1
has a low affinity conformation. The first signal triggered by the TC complex induce
conformational changes in LFA-1 in such a way that LFA-1 will have a high affinity for
ICAM-1 Expressed on DCs .
Specific T cell Activation: The biochemical Signals That Lead to T
cell Activation
In lymphocytes, two types of functions ( antigen recognition and signaling) are
segregated into different sets of molecules.
The TCR and BCR recognizes antigens, but it is not able to transmit biochemical signals
to the interior of the cell.
The TCR is non-covalently associated with a complex of proteins that are involved in
signaling: CD3 and the ζ chain. (The TCR, CD3, and ζ chain make up the TCR complex).
Other molecules involved in triggering signaling
that is involved in T cells activation includes:
CD4/CD8 co-receptors upon becoming bind
to MHCI/MHCII respectively
CD28 which binds to B-7 co-stimulatory molecules
on DCs
NON SPSECIFIC ACTIVATION OF T CELLS
T cells can also be activated experimentally by molecules that bind to the TCRs of many or
all clones of T cells, regardless of the peptide-MHC specificity of
the TCR.
These polyclonal activators of T cells include
1. Antibodies specific for the TCR or associated CD3 proteins
2. Polymeric carbohydrate-binding proteins such as phytohemagglutinin
3. Certain microbial proteins called superantigens. (Microbial super-antigens may cause
serious disease by inducing excessive cytokine release from many T cells.)(the mediate
non-specific binding of TCRs with MHC-II molecules)
Polyclonal activators often are used as experimental tools to study T cell
responses and in clinical settings to test for T cell function or to prepare metaphase
spreads for chromosomal analyses.
ROLE OF ADHESION MOLECULES IN T CELL RESPONSES
Adhesion molecules on T cells recognize their ligands on DC and stabilize the binding of
the T cells to the DCs.
Most TCRs bind the peptide- MHC complexes for which they are specific with low
affinity.
To induce a productive response, the binding of T cells to DCs must be stabilized for a
sufficiently long period that the necessary signaling threshold is achieved.
This stabilization function is performed by adhesion molecules on the T cells LFA-1 (
whose ligands are expressed on DCs (ICAM-1)
The most important of these adhesion molecules belong to the family of proteins called
integrins.
The major T cell integrin involved in binding to DCs during the activation process is the
Leukocyte function–associated antigen-1 (LFA-1), whose ligand on DCs is called
intercellular adhesion molecule-1 (ICAM-1).
Source of signaling involved in Co-nversion of LFA-1 integrin from low affinity to high
affinity:
On resting naive T cells, the LFA-1 integrin is in a low-affinity state. But during T cell
activation
1- Antigen recognition by a T cell: signaling from TCR complex causes LFA-1 on naive
cells to convert to its high affinity state . As a result, T cells bind strongly to APCs providing
a positive feedback loop
2- If a T cell is exposed to chemokines produced as part of the innate immune response to
infection. Chemokine receptor on T cells initiate a signal that convert LFA-1 molecules to
a high-affinity state. T cells bind strongly to APCs ( this usually happens at infection sites,
such as infected macrophages)
Note:
Integrins also play an important role in directing the migration of effector T cells from the
circulation to sites of infection.
ROLE OF CO-STIMULATION IN T CELL ACTIVATION
The full activation of T cells is dependent on the recognition of co-stimulators on DCs
“second signals” for T cell activation
A-
B7-1 (CD80) and B7-2 (CD86)
Both of which are expressed on DCs and whose expression is greatly increased when the
APCs encounter microbes and/ or exposed to cytokines .
B7 proteins are recognized by a receptor called CD28, which is expressed on virtually all
naïve T cells.
Signals from CD28 on T cells binding to B7 on APCs work together with signals generated by
binding of the TCR and co-receptor to peptide-MHC complexes on the same APCs that
activate T cells
.
B-
CD40 ligand:
First and second signals induce the expesstion of CD40 L on T cells being activated
CD40L is expressed on an antigen- stimulated T cells
CD40 L binds to CD40 on DCs
This will activates the DCs to express more and more B7 co-stimulators and may
also start secreting cytokines,
This will enhance T cell activation (amplification of the second signal)
Important Note:
The requirement for co-stimulation ensures that naive T lymphocytes are activated
fully by microbial antigens, and not by harmless foreign substances, because, as stated
previously, microbes stimulate the expression of B7 co-stimulators on APCs
If a naïve T cells recognize a peptide antigen on APC with high affinity in the absence
of costimulation, this results in inactivation of these T cells ( Anergy/Peripheral
tolerance)
Practical Importance of Co-Stimulators on APCs
Protein antigens, such as those used in vaccines, fail to elicit T cell–dependent immune
responses unless these antigens are administered with substances that activate APCs,
including dendritic cells and macrophages (and possibly B cells as well).
Such substances are called adjuvants, and they function mainly by inducing the expression
of co-stimulators on APCs and by stimulating the APCs to secrete cytokines that activate T
cells.
Enhancing the expression of co-stimulators may be useful for stimulating T cell responses
(e.g., against tumors)
Blocking co-stimulators may be a strategy for inhibiting unwanted responses. Agents that
block B7:CD28 interaction are used in the treatment of rheumatoid arthritis and other
inflammatory diseases,
Antibodies to block CD40:CD40L interactions are being tested in inflammatory diseases
and in transplant recipients to reduce or prevent graft rejection.
Inhibitory Proteins Receptors Homologous to CD28
Are Critical for Limiting and Terminating Immune Responses.
The prototypes of the inhibitory receptors are
1. CTLA-4, which, like CD28, recognizes B7 on APCs to give an inhibitory signal
2. PD-1, which recognizes different but related ligands on many cell types. Once PD-1
binds to its ligand, it triggers an inhibitory signal
Both CTLA-4 and PD-1 are induced on activated T cells. The importance of these
molecules appeared in certain situations such as:
Genetic deletion of these molecules in mice results in excessive lymphocyte expansion
and autoimmune disease
CTLA-4 also is involved in inhibiting responses to some tumors
PD-1 inhibits responses to some infections and allows the infections to become
chronic.
Many fundamental questions about when these inhibitory pathways become active,
how the choice between activation and inhibition is determined, and how these
inhibitory receptors work to shut off lymphocytes, remain to be
answered.????????????????????
STIMULI FOR THE ACTIVATION OF CD8+ T CELLS
The activation of CD8+ T cells starts with recognition of class I MHC–associated
peptides on APCs.
However, completion of the activation process requires:
1- Co-stimulation by B-7 expressed on DC ( as in the case of CD4 T cell activation)
and / or
2- Cytokines from helper CD4 T cells that concomitantly activated along with CD8 T
cells
CD8 activation may require the concomitant activation
of CD4+ helper T cells.
When virus-infected cells are ingested by host dendritic cells and the viral antigens
are cross-presented by the DCs, the same DC may present antigens on both MHC I
and MHC II
Thus, both CD8+ T cells and CD4+ T cells specific for viral antigens are activated near
one another.
The CD4+ T cells may produce cytokines or membrane molecules that help to
activate CD8+ T cells.
Cross-presentation:
CD8 activation needs help
from CD4+ effector T cells
CD8 activation DOES NOT
need help from CD4+ effector
T cells
Why HIV infected patients fail to mount an immune response involving CD8 T
cells activation against MANY viral infections?
Severe decrease in the number of helper CD4+ T cells killed by HIV virus in AIDS
patients adversely affect CD8 activation in response to many viral infections
Note: responses to SOME viruses do not appear to require help
from CD4+ T cells, for reasons that are not known.
Functional Responses of T Lymphocytes to
Antigen and Co-Stimulation
The recognition of antigen and co-stimulators molecules (B7) by T cells LEAD TO a
set of responses that results in:
A. Clonal expansion of activated T cells ( proliferation)
B. Differentiation of the naive T cells into effector cells and memory cells
During the process of T cells activation, T cells undergo several changes. Some of
these changes are mediated by cytokines that are produced by T cells themselves
during their activation. These cytokines can act on the T cells themselves (
autocrine effect). In addition, these cytokines may affect many other cells involved
in immune defenses ( Paracrine effect)
Phases of T Cell Responses
SECRETION OF CYTOKINES AND EXPRESSION OF CYTOKINE
RECEPTORS BY ACTIVATED T CELLS
In response to recognition of both the peptide antigen and co-stimulators (B7), T
lymphocytes, especially CD4+ T cells, rapidly secrete several different types of cytokines
that have diverse activities
The first cytokine to be produced by CD4+ T cells, within 1 to 2 hours during the
activation process, is IL-2.
The high-affinity receptor for IL-2 is a three chain molecule. However, Naive T cells
express two signaling chains of this receptor but do not express the chain that enables
the receptor to bind IL-2 with high affinity.
Within 2 hours after the initiation of activation process, the T cells produce the third
chain of the receptor and now the complete IL-2 receptor is able to bind IL-2 strongly.
Note: Naive T cells express the low-affinity IL-2 receptor (IL-2R)
complex, made up of the β and γ(c) chains
(γc) chain designates the common γ chain (γc). It is called so because
it is a common component of several cytokine receptors.
Upon activation of T cells by peptide antigen recognition and
recognition and co-stimulators (B7), the T cells being activated starts
to produce IL-2. At the same time, these T cells express the α chain
of the IL-2R ( the third chain that will complete IL-2 receptor), which
associates with the β and γc chains to form the high-affinity IL-2
receptor. Binding of IL-2 to its receptor initiates proliferation of the T
cells being activated.
Thus, IL-2 produced by antigen-activated T cells preferentially
binds to and acts on the same T cells ( autocrine effect)
The principal actions of IL-2 are to stimulate survival and
proliferation of T cells; for this reason IL-2 is also called T cell
growth factor.
IL-2 stimulates T cells to enter the cell cycle and begin to divide,
resulting in an increase in the number of the antigen-specific T
cells. This is called ( CLONAL EXPANSION)
The role of interleukin-2 (IL-2) and IL-2 receptors in CD4+T cell
proliferation:
Naive T cells express the low-affinity IL-2 receptor (IL-2R) complex, made up of the β and γc chains (γc designates the
common γ chain—so called because it is a component of the receptors for several cytokines). On activation by antigen
recognition and co-stimulation, the cells produce IL-2 and express the α chain of the IL-2R, which associates with the β
and γc chains to form the high-affinity IL-2 receptor. Binding of IL-2 to its receptor initiates proliferation of the T cells
that recognized the antigen. APC, antigen-presenting cell.
CD8+ T lymphocytes that recognize antigen and costimulators do not appear to secrete large amounts of IL-2
Activated CD8 T cells proliferate prodigiously during immune responses.
Antigen recognition and co-stimulation are able to drive the proliferation
of CD8+ T cells without a requirement for much IL-2.
However, in some cases, CD8+ T lymphocytes activation requires help
from CD4+ helper cells to achieve full activation
CLONAL EXPANSION
Within 1 or 2 days after activation, T lymphocytes begin to proliferate, resulting in
expansion of the antigen-specific clone that was activated in response to recognition of
the microbial ( or foreign) peptide antigen on MCH and co-stimulatory molecules (B7).
This expansion helps the adaptive immune response to produce a large pool of antigenspecific lymphocytes from which effector cells can be generated to combat (fight)
infection
Clonal Expasion of Activated CD8 + T cells:
The magnitude of CD8+ T cells clonal expansion is remarkable.
At the peak of some viral infections, which may be within a week after the infection, as
many as 10% to 20% of all of the CD+ T cells population in the body are the ones that
are effector cells to combat the virus that causes infection and initiated the immune
response. It is estimated that clonal expansion of a particular clone of CD8+ T cells may
involve more than 100,000-fold increase in the number of CD8+ T cells specific for the
virus that triggered the immune response
Clonal Expansion of Activated CD4+ T cells((appears to be much
less than that of CD8+ cells))
The magnitude of clonal expansion of CD8+ T cells and CD4+ T cells may reflect
differences in their functions.
CTLs are effector cells that themselves kill infected cells, so that many CTLs may
be needed to kill large numbers of infected cells.
By contrast, each CD4+ effector cell secretes cytokines that activate many other
effector cells such as macrophages , B cells, and even CD8 T cells.
So a relatively smaller number of cytokine producers helper T cells may be
needed to combat infection
Special Features of Clonal Expansion:
First, this enormous expansion of T cells specific for a microbe is
not accompanied by a detectable increase in “bystander” cells
that do not recognize that microbe.
Second, even in infections with complex microbes that contain
many protein antigens, a majority of the expanded clones are
specific for only a few, and often less than five immunodominant
peptides of that microbe.
.
Differentiation of Naïve T Cells Into Effector Cells
Differentiated effector CD4+ or CD8+ T cells start to appear within 3 or 4 days after
exposure to microbes.
The differentiation process involves of changes in gene expression (e.g., the
activation of genes encoding cytokines in CD4 + and CD8+ T cells or cytotoxic proteins
production in CD8+ T cells ( granzyme and perforin).
After differentiating into effector cells, these cells leave the peripheral lymphoid organs and
migrate to the blood stream and then to infection site ( some helper T cells migrate to the
margin of B cell zone to help activating B cells)
At infection sites , effector T cells ( CD4+/helper and CD8/cytotoxic) again encounter the
microbial antigens presented on MHC molecules ((on MHC-II on macrophages and B cells,
and MHC-I on infected cells ) and get ACTIVATED ( this activation is different from
activation of naïve T cells). In this case, upon recognition of microbial peptide antigens ,
effector T cells respond in ways that serve to eradicate infected cells ( cytotoxic T cells)
or activation of macrophages ( helper T cells) to kill or arrest replication of intracellular
microbes that replicate within macrophages ( in phagosome), or helping in B cell
activation
CD4+ Effector T cells (helper T cells)
Helping of other cells by helper T cells is mediated by
1- Surface molecules ( CD40L)
2- Cytokines
These molecules are important in the activation of phagocytes and B lymphocytes ( the
cells the CD4 helper cells help)
1- Role of Surface molecules ( CD40L) of helper cells in the activation of
phagocytes and B lymphocytes (the cells the CD4 helper cells help)
The most important cell surface protein involved in the effector function of helper T cells
is CD40 ligand (CD40L).
The CD40L gene is expressed in activated CD4+ T cells
CD40L binds to its receptor, CD40, which is expressed mainly on macrophages, B
Lymphocytes ((and dendritic cells))
Engagement of CD40 L (on effector helper T cells) with CD40 ( on macrophages and B
cells) activates these cells
Note:
Remember that interaction of CD40L expressed on T cells at the beginning of the
activation process of NAÏVE T cells. In this case, binding of CD40L on T cells to CD40 on
dendritic cells results in increase expression of co-stimulators on DCs ( B7) (feed back
loop to amplify the second signal)
In addition, binding of CD40 L on T cells to CD40 on DC, stimulate the production of
certain cytokines by DCs that affect the activation and Differention of T cells (mainly +
T cells)
The molecules involved in the effector
functions of CD4+ helper T cells.
CD4+ T cells that have differentiated into
effector cells express CD40L and secrete
cytokines.
CD40L binds to CD40 on macrophages or
B lymphocytes, and cytokines bind to
their receptors on the same cells (
macrophages and B cells)
The combination of signals delivered by
CD40 and cytokine receptors activates
macrophages in cell-mediated immunity
(A) and activates B cells to produce
antibodies in humoral immune responses
(B).
2- Role of Cytokine produced by effector helper T cells in the activation of
phagocytes and B lymphocytes ( the cells the CD4 helper cells help)
It has been known for many years that the immune system responds very differently to
different microbes.
For instance, intracellular microbes such as Mycobacterium tuberculosis are ingested by
phagocytes but resist intracellular killing. The adaptive immune response to such microbes
results in the activation of the phagocytes to kill the ingested microbes (provided that the
microbe is within a phagosomal compartment and not in the cytosol).
In striking contrast, helminthic parasites are too large to be phagocytosed, and the
immune response to helminths is dominated by the production of immunoglobulin E (IgE)
antibodies and the activation of Eosinophils . IgE antibody binds to the helminths, and
Eosinophils destroy the helminths by recognition of the Fc region of IgE antibodies bound
to the parasite ( ADCC).
Both types of immune responses are dependent on CD4+ helper T cells, but for many
years it was not clear how the CD4+helper cells are able to stimulate such distinct immune
effector mechanisms.
This puzzle was answered by the discovery of functionally distinct
subpopulations of CD4+ effector T cells that are distinguished by the
cytokines they produce, Th1 and Th2 helper T cells
CD4+ helper T cells may differentiate into several subsets of effector cells
that produce distinct sets of cytokines that perform different functions
There are 4 subsets of helper T cells, these are
1)
2)
3)
4)
TH1 cells ( helper 1)
TH2 cells ( helper 2)
TH17 cells because its signature cytokine is IL-17.
Regulatory T cells play role in immunologic peripheral tolerance [unresponsiveness].
TH1 and TH2 cells may be distinguished based on:
1. The cytokines they produce
2. The cytokine receptors they express
3. Adhesion molecules they express
Note: Comparable data are not yet available for the TH17 subset. It also is likely that
many activated CD4+ T cells produce various mixtures of cytokines and therefore cannot
be readily classified into these subsets.
TH1 cells cytokines:
These cytokines activate macrophages to increase their phagocytic activity as well as
to increase their killing activity of microbes inside them . These are key component of
cell-mediated immunity
The most important cytokine produced by TH1 cells is interferon-γ(IFN-γ),
1- IFN-γ is a potent activator of macrophages that will increase their killing activities (
this will kill microbes inside these macrophages or at least restrict its replication)
2- IFN-γ also stimulates the production of antibody isotypes such as IgG ( class
switching IgM to IgG) that have the following functions:
A- promote the phagocytosis of microbes ( promote opsonization such as IgG)
((because these antibodies bind directly to phagocyte Fc receptors))
B- Activate complement, generating products that bind to microbial surface. phagocyte
complement receptors. Bind to these complement products by complement receptors (
promote opsonization)
3- IFN-γ also stimulates the expression of class II MHC molecules and B7 costimulators on macrophages and dendritic cells, and this action of IFN-γ may serve
to amplify T cell responses.
4- TH1 cells may also produce TNF-alpha
TH2 cytokines: FUNCTIONS
1- Stimulate Eosinophil-mediated immunity, which is especially effective against
helminthic parasites
1- IL-4, which stimulates the production of IgE antibodies ( class switching)
2- IL-5, which activates Eosinophils to increase the expression of Fc-epsilon-R2.
IgE antibodies bind to parasites . Eosinophils have Fc receptor of IgE antibody ( ADCC)
….killing of the parasite
2- Barrier immunity:
IL-4 and IL-13, promote the expulsion of parasites from mucosal organs and inhibit
the entry of microbes by stimulating mucus secretion.
This type of host defense sometimes is called “barrier immunity” because it blocks
the entry of microbes at mucosal barriers.
IgE activates mast cells ( Type I hypersensitivity-discussed later)
3- Tissue repair: Th2-mediated macrophage activation that enhances certain functions
of macrophages such as synthesis of substances involved in tissue repair such as
extracellular matrix proteins as well as activation of fibroblast which also produce
substances of extracellular matrix .
4- Inhibition of the microbicidal activities of macrophages:
Some Th2 cytokines , such as IL-4, IL-10, and IL-13, inhibit the microbicidal activities of
macrophages and thus suppress Th1 cell–mediated immunity.
(IL-4, IL-10, and IL-13 cytokines interfere with the effect of TH1 cytokines that increase
the killing activity of macrophages )
Therefore, the efficacy of cell-mediated immune responses against a microbe may be
determined by a balance between the activation of Th1 and Th2 cells in response to that
microbe.
TH17 Function:
TH17 cells secrete the cytokines IL-17 and IL-22 and are the principal mediators of
inflammation in a number of immunologic reactions against bacterial and fungal
infections and maintaining epithelial barrier functions (production of anti-microbial
peptides)
IL-17 and IL-22 : (Based on animal models), these cytokines have been shown to be
involved in multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis,
and is increasingly being implicated in these diseases in humans.
The functions of TH1 cells.
TH1 cells produce the
cytokine interferon-γ (IFN-γ),
which activates phagocytes to kill
ingested microbes and stimulates
the production of antibodies that
promote the ingestion of
microbes by the phagocytes.
The functions of TH2 cells.
TH2 cells produce the cytokines IL-4,
which stimulates the production of
immunoglobulin E (IgE) antibody.
IL-5, which activates eosinophils.
IgE participates in the activation of
mast cells by protein antigens and coats
helminthes, and eosinophils destroy
the helminthes.
.
The functions of TH17 cells. TH17 cells
produce the cytokines IL-17, which
induces production of chemokines and
other cytokines from various cells.
Recruitment of neutrophils (and
monocytes, not shown) into the site of
inflammation.
Some of the cytokines made by TH17
cells, notably IL-22, function to maintain
epithelial barrier function in the
intestinal tract and other tissues such as
production of antimicrobial peptides.
During the activation process of CD4 T cells…… the development of TH1, TH2,
and TH17 subsets is NOT a random process but is regulated by the stimuli that
naive CD4+ T cells receive during the activation process when they encounter
microbial antigens
I- The Development of TH1 cells :
In response to many bacteria and viruses , dendritic cells and macrophages produce
a cytokine called IL-12, and NK cells produce IFN-γ.
During the activation of naive CD4 T cells , exposure to such cytokines promote the
differentiation of the T cells to the TH1 subset.
Accordingly, the innate immune response—in this case, IL-12 production by DCs and
IFN-γ production by NK cells—influences the nature of the subsequent adaptive
immune response, driving it toward TH1 cells.
II- The development of TH2 cells is stimulated by the cytokine IL-4
The main source of IL-4 is TH2 cells.
It appears that if an infectious microbe does not induce IL-12 production by DCs,
as may be the case with helminths, the T cells themselves are programmed
produce IL-4 spontaneously ( in other words, in the absence of IL-12, CD4 T cells
automatically, produce IL-4 during the activation process that derive their
differentiation into TH2)
Another source for IL-4: Helminths may activate cells of the mast cell lineage to
secrete IL-4, which also promote differentiation of CD4 T cells to the TH2 subset.
III The development and maintenance of TH17 cells
The differentiation of CD4 T cells into TH17 cells require the exposure of these cells to
certain inflammatory cytokines during the activation process such as
IL-6 and IL-1 (produced by macrophages and dendritic cells)
IL-23 (which is related to IL-12 and made by the same cells)
Transforming Growth Facto-beta TGF-β (particularly in mice).
Defining the stimuli for development of this T cell subset is an area of active investigation
The differentiation of CD4+ helper T cells into TH1, TH2, and TH17 subsets is
an excellent example of the specialization of adaptive immunity, illustrating
how immune responses to different types of microbes are designed to be
most effective against these microbes.
Important Notes:
Once one of these populations helper T cells develops, it produces cytokines
that enhance the differentiation of T cells toward that subset and inhibits
development of the other populations.
This “cross-regulation” may lead to increasing polarization of the response
toward one population.
There is emerging evidence that some differentiated CD4+ T cells can convert
from one subset into another, under certain conditions
CD8+ T lymphocytes activated by antigen and co-stimulators
differentiate into Cytolytic T Cells (CTLs )/ also called Cytotixic T
cells
Effector CD8+ T cell (CTLs) kill infected cells that display microbial peptides on MHC-I
by :
A- Secreting Proteins that create pores in the membranes of the infected cells perforin
and Granzyme that induce apoptosis ( by activating caspases) in infected cells
B- In addition Effector CD+T cells express Fas ligand ( death ligand) . Binding of Fas L (
death ligand) on Effector CD8+ T cell to Fas Receptor (Death receptor) on infected cells
activate caspases in infected cells that lead to apoptosis
The evidence of differentiation of naive CD8+ T cells into effector CTLs is the production
of the molecules/proteins ( mentioned above) that are needed to kill infected cells.
DEVELOPMENT OF MEMORY T LYMPHOCYTES:
A fraction of antigen-activated T lymphocytes differentiates into long-lived memory
cells. However, they require signals delivered by certain cytokines, including IL-7, in
order to stay alive.
Factors involved in determining whether the progeny of antigen-stimulated
lymphocytes will differentiate into effector cells or memory cells are not known
Memory T cells can be found in lymphoid organs, in mucosal tissues, and in the
circulation.
Memory T cells do not continue to produce cytokines or kill infected cells , but they may
do so rapidly on encountering the antigen that they recognize after undergoing rabid
clonal expansion.
DECLINE OF THE IMMUNE RESPONSE:
During an immune response , a very high number of antigen-specific effector T
lymphocytes are generated to combat infection
Once the microbe is eradicated, the system has to return to its steady state, called
homeostasis ( this implies that most of the generated effector T cells need to be
eliminated- MISSION ACOMBLISHED) , so that the immune system is prepared to
respond to the next infectious pathogen.
During an immune response against a particular microbe, activation, proliferation ,
differentiation of naïve T cells as well as survival of effector T cells are maintained by:
1. Continuous detection of the microbial antigen
2. Co-stimulatory signals from CD28 ( by binding to be B7 on Macrophages and B
cells),
3. Cytokines such as IL-2.
Once an infection is cleared and the stimuli for naïve T lymphocyte activation and
survival if effector cells disappear
As a result, these effector cells start to cells die by a process of apoptosis (programmed
cell death).
The immune response starts to subside/ decline within 1 or 2 weeks after the infection
has been eradicated.
The only sign/evidence about the occurrence of a T cell–mediated immune response
against a particular microbe is the detection of a pool of surviving memory T lymphocytes
specific to that microbe.