CHAPTER 10: Differentiation and Functions of CD4+ Effector T
Cells
Cell-mediated immunity: Defense against microbes that is
mediated by T cells
T cells:
- Provide protection against intracellular and extracellular
pathogens
- Also assist in the elimination of tumor cells.
- Enhance killing of microbes that normally survive outside
cells but are ingested by phagocytes.
- Defects in cell-mediated immunity result in increased
susceptibility to infection by viruses, bacteria, extracellular
bacteria and fungi that are eliminated by phagocytes.
Adaptive immunity can be divided into humoral immunity and cell
mediated immunity.
- Humoral immunity: can be transferred from an immunized
donor to a naive host by antibodies
• Neutralizes and eliminates extracellular microbes and
toxins that are accessible to antibodies; antibodies
enhance phagocytosis of extracellular microbes
- Cell-mediated immunity: can be transferred by T
lymphocytes.
T cells are divided into two major classes: CD4+ and CD8+
CD4+ effector T lymphocytes:
- Produce cytokines that mediate their functions.
- Serve a critical role in phagocyte-mediated elimination of
microbes
- Activate other leukocytes, including neutrophils and
eosinophils, and stimulate antibody production by B cells.
CD8+ effector:
- Capable of killing infected and tumor cells
- Responsible for the eradication of viruses, that survive and
replicate inside any cell, including nonphagocytic cells.
OVERVIEW OF CD4+ T CELL-MEDIATED IMMUNE RESPONSES
Sequence of events in the responses of CD4+ T cells:
1. Initial activation of these cells in lymphoid organs to generate
effector and memory cells
2. Migration of effector cells to sites of infection
3. Elimination of infectious pathogens at these sites
 Effector CD4+ T cells are generated in secondary lymphoid
organs, and most of the effector cells leave these organs and
migrate to peripheral sites of infection, where they function
in microbe elimination.
- Migration of effector T cells to sites of infection is dependent
on endothelial adhesion molecules and chemokines
expressed at these sites
- Once in the tissues, the T cells encounter microbial antigens
presented by macrophages and other APCs.
VLA-4 and VLA-5 (very late antigens-4 and -5): integrins which
bind to fibronectin in extracellular matrices
CD44: Highly expressed on activated T cells which binds to
hyaluronan.
- Chemokine receptors expressed on activated T cells bind
chemokines that are produced in tissues.
- As a result of these adhesive and chemotactic interactions,
antigen-specific effector T cells that encounter the antigen
are preferentially retained at the extravascular site.
- T cells not specific for the antigen that migrate into a site of
inflammation may die in the tissue or return to the circulation
through lymphatic vessels.
- Some memory T cells also migrate to peripheral tissues, using
the same adhesion molecules and chemokine receptors as do
effector cells.
Fraction of the CD4+ T cells that are activated in secondary
lymphoid organs do not exit the organs but migrate into lymphoid
follicles within the organs, where they help B cells to produce
high-affinity antibodies of different isotypes.
 In cell-mediated immune responses against phagocytosed
microbes, T cells specifically recognize microbial antigens,
but phagocytes actually destroy the pathogens.
- Effector T cells of the CD4+ lineage link specific recognition of
microbes with the recruitment and activation of other
leukocytes that destroy the microbes.
- First appreciated from studies of cell-mediated immunity to
the intracellular bacterium L. monocytogenes
- Shown that mice previously infected with a low (sublethal)
dose of Listeria were protected from challenge with higher
doses that were lethal in previously uninfected animals.
- Protection could be transferred to naive animals with
lymphocytes from the infected mice but not with serum, the
fluid fraction of clotted blood that contains antibodies.
 Ingestion and elimination of microbes by phagocytes is also
a major reaction of innate immunity, but T cells greatly
enhance this function of phagocytes.
- Phagocytes: recognize microbes and are activated by
microbial ligands; also capable of destroying a variety of
microbes.
- However, many infectious pathogens have evolved to resist
this mechanism of innate immunity and can survive and even
replicate inside macrophages.
- In these situations, T cells recognize microbial protein
antigens and recruit and activate phagocytes, enabling them
to eradicate infections that may not be combated by innate
immunity alone.
- CD4+ effector T cells activate phagocytes via surface
molecules, CD40 ligand (CD40L), and secreted cytokines.
 Inflammation, consisting of leukocyte recruitment and
activation, accompanies many of the reactions of CD4+ T
lymphocytes and may damage normal tissues.
- T cell–dependent inflammation serves as an antimicrobial
defense mechanism but also can be injurious to tissues.
- When a T cell reaction causes injury, it is called delayed-type
hypersensitivity (DTH)
• DTH frequently occurs together with protective cell-
mediated immunity against microbes and may be the
cause of much of the pathology associated with certain
types of infection and chronic immunologic diseases
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SUBSETS OF CD4+ EFFECTOR T CELLS
 Three major subsets of CD4+ effector T cells, called Th1, Th2
and Th17, function in host defense against distinct types of
infectious pathogens and are involved in different types of
tissue injury in immunologic diseases
Properties of Th1, Th2, and Th17 Subsets
How can the same CD4+ cells elicit such different responses?
ANSWER: CD4+ T cells consist of subsets of effector cells that
produce distinct sets of cytokines, elicit quite different reactions,
and are involved in host defense against different microbes, as
well as in distinct types of immunologic diseases.
- Types 1 and 2 helper T cells, or Th1 and Th2: first two subsets
that were discovered
- Th17: named because its characteristic cytokine is
interleukin-17 (IL-17)
• T cells responsible for some CD4+ T cell–mediated
inflammatory diseases that could not be attributed to
the Th1 and Th2 subsets.
 The defining characteristics of differentiated subsets of
effector cells are the cytokines they produce, which is
related to the transcription factors they express.
Transcription factors are responsible for production of different
cytokines by these subsets as well as expression of different
chemokine receptors and other proteins.
 The signature cytokines produced by the major CD4+ T cell
subsets are interferon (IFN)-γ for Th1 cells; IL-4, IL-5, and IL-
13 for Th2 cells; and IL-17 and IL-22 for Th17 cells
- Cytokines produced by these T cell subsets determine their
effector functions and roles in diseases.
- Some of the cytokines made by each subset also stimulate
the development and expansion of that subset and inhibit
other effector cells, thus contributing to amplification of each
type of helper T cell response, a process called polarization
- The production of distinct sets of cytokines is initiated by the
expression of subset-specific transcription factors and is
sustained by epigenetic modifications of specific cytokine
gene loci.
 Th1, Th2, and Th17 cells each have distinct patterns of
homing, in large part because they express chemokine
receptors and adhesion molecules which direct them to
migrate into different sites of infections.
Th1:
- Express high levels of CXCR3 and CCR5, which bind to
chemokines produced in tissues during innate immune
responses.
- Abundant at sites of infection where the infectious agents
trigger strong innate immune reactions
- Also express high levels of ligands for E-selectin and P-
selectin, which assist in the migration of these cells to sites
of strong inflammation
Th2:
- Express the CCR3, CCR4, and CCR8, which recognize
chemokines that are highly expressed at sites of helminthic
infection or allergic reactions, particularly in mucosal tissues,
Th17: express CCR6, which binds the chemokine CCL20, which is
produced by various tissue cells and macrophages in some
bacterial and fungal infections.
- Antibody responses develop mostly in secondary lymphoid
organs, particularly in germinal centers, where antigen-
specific B and T cells interact.
- The differentiated CD4+ T cells that remain in secondary
lymphoid organs to help B lymphocytes are not classical Th1
or Th2 but Tfh cells that make many of the same cytokines as
Th1 and Th2 cells do
 Different inflammatory diseases are caused by excessive
reactions of different helper T cell subsets.
- In general, Th1 and Th17 cells play prominent roles in
autoimmune diseases associated with inflammation,
whereas allergic reactions are dominated by Th2 cells.
Important caveats with the idea that effector CD4+ T cells can be
classified into clear subsets based on defined criteria:
- Many effector CD4+ T cells produce various combinations of
cytokines or only some of the cytokines characteristic of a
particular subset and are not readily classifiable into
separable populations.
• Some cells may produce cytokines that are not
characteristic of any of the three subsets (such as IL-9)
or are only some of the cytokines produced by a
particular subset.
• This restricted cytokine profile has led to an expanding
nomenclature describing these populations (such as
Th9, Th22, and so on).
- Some of these effector T cells may convert from one cytokine
profile to another by changes in activation conditions.
Development of Th1, Th2, and Th17 Subsets
 Differentiated Th1, Th2, and Th17 cells all develop from
naive CD4+ T lymphocytes, mainly in response to cytokines
present early during immune responses.
The process of effector cell development involves multiple steps:
- Signals that T cells receive from APCs and other cells at the
site of the immune response initiate the conversion of
antigen-stimulated T cells to effector cells.
- Developing effector cells become progressively committed to
a particular cytokine production profile, and cytokines
amplify these differentiation pathways.
- The net result is the progressive accumulation of T cell
populations that produce distinct sets of cytokines.
Several important general features of T cell subset differentiation:
1. The cytokines that drive the development of CD4+ T cell
subsets are produced by APCs (primarily dendritic cells and
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 macrophages) and other immune cells (such as NK cells and
mast cells) present in the lymphoid organ where the
immune response is initiated.
- Dendritic cells that encounter microbes and display microbial
antigens are activated to produce cytokines as part of innate
immune responses to the microbes
• Different microbes may stimulate dendritic cells to
produce distinct sets of cytokines, perhaps because the
microbes are recognized by different microbial sensors
in the cells.
- NK cells and mast cells also produce cytokines that influence
the pattern of T cell subset development.
2. Stimuli other than cytokines may also influence the pattern
of helper T cell differentiation.
- Affinity of the T cell receptor for antigen, the amount of
antigen, and the nature of the APC all determine the subset
that develops following antigen recognition.
- The genetic makeup of the host is an important determinant
of the pattern of T cell differentiation.
 The distinct cytokine profiles of differentiated cell
populations are controlled by particular transcription
factors that activate cytokine gene expression and by
chromatin modifications affecting accessibility of these
factors to the promoters and regulatory elements of
cytokine genes.
- Transcription factors are themselves activated or induced by
signals from antigen receptors, innate immune receptors,
costimulators, and cytokine receptors.
- As the subsets become increasingly polarized, the gene loci
encoding that subset’s signature cytokines undergo histone
modifications & other chromatin remodeling events, so that
these loci remain accessible to RNA polymerase and
transcription factors, whereas the loci for other cytokines are
in an inaccessible chromatin state.
- Thus, the cytokine genes characteristic of a particular subset
become fixed in an antigen responsive state, whereas genes
that encode cytokines not produced by that subset remain
inactive.
- These epigenetic changes are inherited in the progeny of
proliferating cells, thus ensuring that the activated T cells
become committed to one specific pathway.
 Each subset of differentiated effector cells produces
cytokines that promote its own development and may
suppress the development of the other subsets.
IFN-: secreted by Th1 cells; promotes further Th1 differentiation
and inhibits the generation of Th2 and Th17
cells.
IL-4: produced by Th2 cells; promotes Th2 differentiation.
 Differentiation of each subset is induced by the types of
microbes that the subset is best able to combat.
- Development of Th1 cells is driven by intracellular microbes,
against which the principal defense is Th1 mediated.
- Immune system responds to helminthic parasites by the
development of Th2 cells, and the cytokines produced by
these cells are important for combating helminths.
- Th17 responses are induced by some bacteria and fungi and
are most effective at defending against these microbes.
THE Th1 SUBSET
 The IFN-γ–producing Th1 subset is induced by microbes that
are ingested by and have evolved to survive and replicate
within phagocytes and is the major effector T cell
population in phagocyte-mediated host defense.
Th1 cells were the first defined subset of helper T cells shown
to mediate cellular immunity against pathogens that survive
inside phagocytes.
Development of Th1 Cells
 Th1 differentiation is driven mainly by the cytokines IL-12
and IFN-γ and occurs in response to microbes that activate
dendritic cells, macrophages, and NK cells
- CD4+ T cells differentiation to Th1 is stimulated by many
intracellular bacteria, such as Listeria and mycobacteria, and
by some parasites, such as Leishmania, all of which infect
dendritic cells and macrophages.
- Also stimulated by viruses and by protein antigens
administered with strong adjuvants.
Cytokines promoting Th1 development: IL-12, IL-18, and type I
interferons.
IL-12: most potent
IL-18: synergizes with IL-12
Type I interferons: may be important for Th1 differentiation in
response to viral infections, especially in humans.
IFN-γ: stimulated by NK cells; strong Th1-inducing cytokine and
also acts on dendritic cells and macrophages to induce more IL-12
secretion.
- Inhibits the differentiation of naive CD4+ T cells to the Th2
and Th17 subsets, thus promoting the polarization of the
immune response in one direction.
- After Th1 cells have developed, they secrete IFN-γ, which
promotes more Th1 differentiation and thus amplifies the
reaction.
T cells may further enhance cytokine production by dendritic cells
and macrophages by virtue of CD40L on activated T cells engaging
CD40 on the APCs and stimulating IL-12 secretion.
 IFN-γ and IL-12 stimulate Th1 differentiation by inducing
and activating the transcription factors T-bet, STAT1, and
STAT4
T-bet:
- Induced in naive CD4+ T cells in response to antigen and IFN-
γ.
- Member of the T-box family of transcription factors
IFN-γalso activates the transcription factor STAT1, which in
turn stimulates expression of T-bet.
- T-bet then promotes IFN-γ production through a
combination of direct transcriptional activation of the IFNG
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 gene and by inducing chromatin remodeling of the IFN-γ
promoter region.
- The ability of IFN-γ to stimulate T-bet expression and the
ability of T-bet to enhance IFN-γ transcription set up a
positive amplification loop that drives differentiation of T
cells toward the Th1 phenotype. IL-12 contributes to Th1
commitment by binding to receptors on antigen stimulated
CD4+ T cells and activating the transcription factor STAT4,
which further enhances IFN-γ production.
Functions of Th1 Cells
 The principal function of Th1 cells is to activate
macrophages to ingest and destroy microbes
Th1-mediated macrophage activation is involved in injurious DTH,
which is a component of many inflammatory diseases, and in
granulomatous inflammation, which is typical of tuberculosis, and
is also seen in some other infectious and inflammatory disorders.
Interferon-γ
 IFN-γ is the principal macrophage-activating cytokine.
- Also called immune or type II interferon.
- Not a potent antiviral cytokine, functions mainly as an
activator of effector cells of the immune system.
- Homodimeric protein belonging to the type II cytokine family
- Functions as a mediator of innate immunity
- Produced by CD4+ Th1 cells, NK cells and CD8+ T cells
• NK cells secrete IFN-γ in response to activating ligands
on the surface of infected or stressed host cells or in
response to IL-12
• In adaptive immunity, T cells produce IFN-γ in response
to antigen recognition, and production is enhanced by
IL-12 and IL-18.
- Receptors: two structurally homologous polypeptides IFNγR1
and IFNγR2.
• IFN-γ:binds to and induces the dimerization of the two
receptor chains.
▪ Leads to activation of the associated Janus kinases
JAK1 and JAK2 and ultimately to phosphorylation
and dimerization of STAT1, which stimulates
transcription of several genes
1. IFN-γ activates macrophages to kill phagocytosed microbes.
- Macrophage activation resulting in increased microbicidal
activity is called classical macrophage activation, to be
contrasted with an alternative activation pathway that is
induced by Th2 cytokines
2. IFN-γ promotes the differentiation of CD4+ T cells to the Th1
subset and inhibits the development of Th2 and Th17 cells.
- Serve to amplify the Th1 response and were described
earlier.
3. IFN-γ stimulates expression of several different proteins
that contribute to enhanced antigen presentation and T cell
activation
- Includes MHC molecules; many proteins involved in antigen
processing, including components of the proteasome; and B7
costimulators on APCs.
4. IFN-γ acts on B cells to promote switching to certain IgG
subclasses, notably IgG2a or IgG2c (in mice), and to inhibit
switching to IL-4–dependent isotypes, such as IgE.
- IgG subclasses induced by IFN-γ bind to Fcγ receptors on
phagocytes and activate complement; promotes
phagocytosis of opsonized microbes.
- Thus, IFN-γ induces antibody responses that also participate
in phagocyte-mediated elimination of microbes, in concert
with the direct macrophage-activating effects of this
cytokine.
• Established in mice but not in humans.
- The actions of IFN-γ result in increased ingestion of microbes
and the destruction of the ingested pathogens.
- Individuals with inherited loss-of-function mutations in the
IFN-γ receptor, IL-12 receptor, or their signaling molecules
(such as STAT1) are susceptible to infections with microbes
that can survive within macrophages.
Other Th1 Cytokines
- Tumor necrosis factor (TNF) and various chemokines, which
contribute to the recruitment of leukocytes and enhanced
inflammation.
- Th1 cells are also important sources of IL-10, which functions
mainly to inhibit dendritic cells and macrophages and thus to
suppress Th1 activation → Example of a negative feedback
loop in T cell responses.
Th1-Mediated Classical Macrophage Activation and Killing of
Phagocytosed Microbes
 Th1 cells activate macrophages by contact-mediated signals
delivered by CD40L-CD40 interactions and by IFN-γ
Classical pathway of macrophage activation
- Also called M1 macrophages.
- When the Th1 cells are stimulated by antigen, the cells
express CD40L on their surface and secrete IFN-γ.
- The actions of IFN-γ on macrophages synergize with the
actions of CD40L, and together they are potent stimuli for
macrophage activation.
- CD40 signals activate the transcription factors nuclear factor
κB (NF-κB) and activation protein 1 (AP-1)
STAT1 stimulate the expression of several enzymes in the
phagolysosomes of macrophages, including inducible nitric oxide
synthase (iNOS), which stimulates the production of nitric oxide
(NO); and lysosomal enzymes.
 Activated macrophages kill phagocytosed microbes mainly
by the actions of NO, lysosomal enzymes and ROS.
- Produced w/in the lysosomes of macrophages and kill
ingested microbes after phagosomes fuse with lysosomes
- X-linked hyper-IgM syndrome: mutations in CD40L in which
the gene for CD40 or CD40L is knocked out are highly
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 susceptible to infections with microbes, including the fungus
Pneumocystis jiroveci.
- Rare patients make autoantibodies against their own IFN-γ
and are susceptible to disseminated mycobacterial
infections.
- Macrophages activated by Th1 cells stimulate inflammation
through the secretion of cytokines, mainly TNF, IL-1, and
chemokines, and shortlived lipid mediators, such as
prostaglandins, leukotrienes, and platelet-activating factor.
• Collective action of these is to recruit more leukocytes,
which enhances the host’s ability to destroy infectious
organisms.
- May amplify cell-mediated immune responses by becoming
more efficient APCs because of increased levels of molecules
involved in antigen processing and increased surface
expression of class II MHC molecules and costimulators, and
by producing cytokines (such as IL-12) that stimulate T
lymphocyte differentiation into effector cells.
- Some tissue injury may normally accompany Th1 cell–
mediated immune reactions to microbes since microbicidal
products released by activated macrophages and neutrophils
are capable of injuring normal tissue and do not discriminate
between microbes and host tissue.
THE Th2 SUBSET
 The Th2 subset is the mediator of phagocyte-independent
defense, in which eosinophils and mast cells play central
roles.
- Important for the eradication of helminthic infections and
perhaps also for elimination of other microbes in mucosal
tissues.
- Central to the development of allergic diseases
 IL-4 stimulates Th2 development by activating the
transcription factor STAT6, which, together with T cell
receptor (TCR) signals, induces expression of GATA-3
GATA-3:
- Transcription factor that stimulates expression of the Th2
cytokine genes IL-4, IL-5, and IL-13.
- Works by directly interacting with the promoters of these
genes and also by causing chromatin remodeling, which
opens up the locus for accessibility to other transcription
factors.
- Similar to T-bet
- Functions to stably commit differentiating cells toward the
Th2 phenotype, enhancing its own expression through a
positive feedback loop.
- Blocks Th1 differentiation by inhibiting expression of the
signaling chain of the IL-12 receptor.
Functions of Th2 Cells
 Th2 cells stimulate IgE-, mast cell-, and eosinophil mediated
reactions that serve to eradicate helminthic infections and
to promote tissue repair
- Special mechanisms are needed for defense against
helminthic infections since helminths are too large to be
phagocytosed
- Functions of Th2 cells are mediated by the ff:
• IL-5: activates eosinophils
• IL-13: which has diverse actions.
- Tfh: produces IL-4 stimulate the production of IgE antibodies
Interleukin-4
 IL-4 is the signature cytokine of the Th2 subset and functions
as both an inducer and an effector cytokine of these cells.
- Member of the type 1 four–α-helical cytokine family.
- Principal cellular sources are CD4+ T lymphocytes of the Th2
subset and activated mast cells.
- IL-4 receptor consists of a cytokine-binding α chain
associated with the γc chain shared by other cytokine
receptors.
• IL-4Rαγc receptor: signals by a JAK-STAT pathway
involving JAK1, JAK3, and STAT6, and by a pathway that
involves the insulin response substrate (IRS) protein
called IRS-2.
• Activated STAT6 induces transcription of genes that
account for many of the actions of this cytokine.
IL-4 has important actions on several cell types:
1. IL-4 produced by Tfh cells stimulates B cell Ig heavy
chain class switching to the IgE isotype.
- Knockout mice lacking IL-4 have less than 10% of normal IgE
levels.
- IgE antibodies:
• Play a role in eosinophil-mediated defense against
helminthic infections
• Principal mediator of immediate hypersensitivity
(allergic) reactions
- IL-4 also enhances switching to IgG4 (in humans, or the
homologous IgG1 in mice) and inhibits switching to the IgG2a
and IgG2c isotypes in mice, both of which are stimulated by
IFN-γ.
• One of several reciprocal antagonistic actions of IL-4 and
IFN-γ.
2. IL-4 stimulates the development of Th2 effector cells from
naive CD4+ T cells and functions as a growth factor for
differentiated Th2 cells.
3. IL-4, together with IL-13, contributes to an alternative form
of macrophage activation that is distinct from the
macrophage response to IFN-γ.
- IL-4 and IL-13 suppress IFN-γ–mediated classical macrophage
activation and thus inhibit defense against intracellular
microbes that are destroyed by phagocytosis.
4. IL-4 (and IL-13) stimulate peristalsis in the gastrointestinal
tract, and IL-13 increases mucus secretion from airway and
gut epithelial cells.
- Contribute to elimination of microbes at epithelial surfaces.
5. IL-4 and IL-13 stimulate the recruitment of leukocytes,
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- By promoting the expression of adhesion molecules on
endothelium and the secretion of chemokines that bind
chemokine receptors expressed on eosinophils.
Interleukin-13
- Structurally and functionally similar to IL-4 and also plays a
key role in defense against helminths and in allergic diseases.
- Member of the type 1 four–α-helical cytokine family.
- Produced mainly by the Th2 subset, but innate lymphoid cells
and other leukocytes may also produce the cytokine.
- Functional IL-13 receptor is a heterodimer of the IL-4Rα chain
and the IL-13Rα1 chain.
• This complex can bind both IL-4 and IL-13 with high
affinity and also signals through a JAK1, JAK3, and STAT6
pathway.
• Expressed on a wide variety of cells, including B cells,
mononuclear phagocytes, DCs, eosinophils, basophils,
fibroblasts, endothelial cells, and bronchial epithelial
cells.
• T cells do not express the IL-13 receptor.
 IL-13 works together with IL-4 in defense against helminths
and in allergic inflammation.
- Both IL-13 and IL-4 can activate B cells to switch to IgE and
some IgG isotypes and recruit leukocytes, and both are
involved in alternative macrophage activation.
- IL-13 stimulates mucus production by airway epithelial cells,
an important component of allergic reactions, such as
asthma.
- Not involved in Th2 differentiation.
Interleukin-5
 IL-5 is an activator of eosinophils and serves as the principal
link between T cell activation and eosinophilic
inflammation.
- A homodimer of a polypeptide containing a four–α-helical
domain and is a member of the type I cytokine family.
- Produced mainly by Th2 cells and innate lymphoid cells.
- IL-5 receptor is a heterodimer composed of a unique α chain
and a common β chain (βc), which is also part of the IL-3 and
GM-CSF receptors
- Major IL-5–induced signaling pathway involves JAK2 and
STAT3.
 The principal actions of IL-5 are to activate mature
eosinophils and to stimulate the growth and differentiation
of eosinophils.
- Activated eosinophils are able to kill helminths.
- Eosinophils express Fc receptors specific for IgE and some IgG
antibodies and are thereby able to bind to microbes, such as
helminths, that are coated with these antibodies.
Roles of Th2 Cells in Host Defense
1. IgE- and eosinophil-mediated reactions.
- IL-4 (and IL-13) stimulate the production of helminth-specific
IgE antibodies, which bind to antigens on the helminths and
promote the attachment of eosinophils, through their Fc
regions.
- IL-5: activates the eosinophils, and these cells release their
granule contents, including major basic protein and major
cationic protein, which are capable of destroying even the
tough integuments of helminths
2. Host defense at mucosal barriers.
- Th2 cells play an important role in host defense at the
barriers with the external environment (barrier immunity)
• Cytokines produced by Th2 cells are involved in blocking
entry and promoting expulsion of microbes from
mucosal organs, by increased mucus production and
intestinal peristalsis.
3. Alternative macrophage activation and tissue repair.
- IL-4 and IL-13 activate macrophages to express enzymes that
promote collagen synthesis and fibrosis.
Alternative macrophage activation (M2):
- Macrophage response to Th2 cytokines
- Results in potent microbicidal functions and inflammation
- Produce cytokines that terminate inflammation and initiate
repair after diverse types of tissue injury.
- Induce scarring and fibrosis by secreting growth factors that
stimulate fibroblast proliferation, collagen synthesis, and
new blood vessel formation or angiogenesis.
- Th2 cytokines also suppress classical macrophage activation
and interfere with protective Th1-mediated immune
responses to intracellular infections.
THE Th17 SUBSET
 The Th17 subset is primarily involved in recruiting
neutrophils and, to a lesser extent, monocytes to sites of
infection and inflammation.
- Critical for destroying bacteria and fungi, microbes that are
killed by the phagocytes, and also contribute significantly to
inflammatory diseases.
Development of Th17 Cells
 The development of Th17 cells is stimulated by
proinflammatory cytokines produced in response to
bacteria and fungi
- Bacteria and fungi act on DCs and stimulate the production
of cytokines, including IL-6, IL-1, and IL-23, all of which
promote differentiation of CD4+ T cells to the Th17 subset.
• Engagement of the lectin receptor Dectin-1 on dendritic
cells b fungal glucans is a signal for the production of
these cytokines.
- May also be produced not only in response to particular
microbes, but also when cells infected with various bacteria
and fungi undergo apoptosis and are ingested by DCs.
- IL-6 and IL-1: stimulate the early steps in Th17 differentiation
- IL-23: more important for the proliferation and maintenance
of differentiated Th17 cells.
- TGF-β: anti-inflammatory cytokine w/c promotes the
development of proinflammatory Th17 cells when other
mediators of inflammation, such as IL-6 or IL-1, are present.
- Th17 differentiation is inhibited by IFN-γ and IL-4; strong Th1
and Th2 responses tend to suppress Th17 development.
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 The development of Th17 cells is dependent on the
transcription factors RORγt and STAT3
- TGF-β, IL-6 and IL-1, work cooperatively to induce the
production of RORγt
• RORγt
- Transcription factor that is a member of the retinoic
acid receptor family
- T cell–restricted protein encoded by the RORC gene,
sometimes called RORc.
- IL-6, activate the transcription factor STAT3, which
functions with RORγt to drive the Th17 response.
- Th17 cells appear to be abundant in mucosal tissues & GI
tract, suggesting that the tissue environment influences the
generation of this subset, perhaps by providing high local
concentrations of TGF-β and inflammatory cytokines.
- Th17 cells may be especially important in combating
intestinal infections and in the development of pathologic
intestinal inflammation.
- The development of Th17 cells in the GI tract is dependent on
the local microbial population
Functions of Th17 Cells
 Th17 cells combat microbes by recruiting leukocytes, mainly
neutrophils, to sites of infection
- Th17 cells play an important role in defense against these
infections.
- Most of the inflammatory actions of these cells are mediated
by IL-17
Interleukin-17
- Unusual cytokine because neither it nor its receptor is
homologous to any other known cytokine-receptor pair.
- IL-17 family includes six structurally related proteins, of
which IL-17A and IL-17F are the most similar
- Immunologic functions of this cytokine family are mediated
primarily by IL-17A.
• IL-17A: produced by Th17 cells as well as innate
lymphoid cells and some γδ and CD8+ T cells.
- IL-17 receptors are multimeric and expressed on a wide range
of cells
- Important link between T cell–mediated adaptive immunity
and the acute inflammatory response
IL-17 has several important functions in host defense:
1. IL-17 induces neutrophil-rich inflammation.
- Stimulates the production of chemokines and other cytokines
that recruit neutrophils and, to a lesser extent, monocytes to
the site of T cell activation.
- Also enhances neutrophil generation by increasing the
production of granulocyte colony-stimulating factor (G-CSF)
and the expression of its receptors.
2. IL-17 stimulates the production of antimicrobial substances,
Other Th17 Cytokines
1. IL-22:
- Member of the type II cytokine family.
- Produced by activated T cells, particularly Th17 cells, and by
some NK cells and innate lymphoid cells.
- Produced in epithelial tissues, especially of the skin and GI
tract
- Serves to maintain epithelial integrity, mainly by promoting
the barrier function of epithelia, by stimulating repair
reactions, and by inducing production of antimicrobial
peptides.
- Also contributes to inflammation, in part by stimulating
epithelial production of chemokines, and may therefore be
involved in tissue injury in inflammatory diseases.
2. IL-21:
- Produced by activated CD4+ T cells, including Th17 cells and
Tfh cells.
- Belongs to the type I cytokine receptor family, consists of a
ligand-binding chain and the γc subunit
- Activates a JAKSTAT signaling pathway in which STAT3 is
especially prominent.
- Important function is in antibody responses, especially the
reactions that occur in germinal centers
- Required for the generation of Tfh cells and activates B cells
in germinal centers.
- Has also been shown to promote the differentiation of Th17
cells, especially in humans, providing an autocrine pathway
for amplifying Th17 responses.
- Other reported actions include increasing the proliferation,
differentiation, and effector function of CD8+ T cells and NK
cells.
Roles of Th17 Cells in Host Defense
 The principal function of Th17 cells is to destroy extracellular
bacteria and fungi, mainly by inducing neutrophilic
inflammation
- The importance of this role of Th17 cells is illustrated by the
inherited disease called Job syndrome (or hyper-IgE
syndrome)
- Job syndrome (or hyper-IgE syndrome):
• Caused by mutations in STAT3 resulting in defective
Th17 development, and is characterized by increased
susceptibility to cutaneous fungal and bacterial
infections.
- Defective Th17 function is also associated with chronic
mucocutaneous candidiasis.
• Surprisingly, patients with mutations in the RORC gene,
which encodes RORγt, the canonical transcription factor
for Th17 cells, show defects not only in IL-17 production
but also in the production of IFN-γ, the classical Th1
cytokine.
 Th17 cells contribute to the pathogenesis of many
inflammatory diseases.
- Th17 responses have been associated with psoriasis,
inflammatory bowel disease, rheumatoid arthritis, and
multiple sclerosis.
7 | CAÑETE, DNP
 • Agents that block the development or functions of Th17
cells are in clinical trials for several of these diseases and
are approved for the treatment of psoriasis.
• Role of Th17 cells in these inflammatory bowel disease
and rheumatoid arthritis is uncertain.
- Both Th1 and Th17 cells may be present in the lesions in
various inflammatory diseases, and both may contribute to
the development and propagation of these disorders.
 Th17 cells help to maintain the integrity of epithelial
barriers, such as in the intestinal tract.
IL-22 promotes the regeneration of epithelia.
Possible that different subsets of Th17 cells are involved in this
protective function and in the pathogenic roles of this
subset.
FUNCTIONS OF OTHER T CELL SUBSETS
Their functions may include the following:
1. Early defense against microbes encountered at epithelia,
before adaptive immune responses have developed
2. Surveillance against stressed cells, such as cells that have
undergone DNA damage or are infected, and elimination of
these cells
3. Production of cytokines that influence later adaptive immune
responses.
γδ T Cells
- T cells expressing the γδ TCR represent a lineage distinct from
the more numerous αβ-expressing T cells.
- Percentages of γδ T cells vary widely in different tissues and
species, but overall, less than 5% of all T cells express this
form of TCR.
- The γδ heterodimer associates with the CD3 and ζ proteins in
the same way as TCR αβ heterodimers do, and TCR-induced
signaling events typical of αβ-expressing T cells are also
observed in γδ T cells.
- Only a limited number of γ and δ V regions are expressed, and
there is little or no junctional diversity.
 Different populations of γδ T cells may develop at distinct
times during ontogeny, contain different V regions in their
antigen receptors, reside in different tissues, and have a
limited capacity to recirculate among these tissues.
- Abundance in epithelial tissues of certain species.
• e.g. more than 50% of lymphocytes in the small bowel
mucosa of mice and chickens, called intraepithelial
lymphocytes, are γδ T cells.
• In mouse skin, many of the intraepidermal T cells express
the γδ receptor.
• Equivalent cell populations are not as abundant in
humans; only approximately 10% of human intestinal
intraepithelial T cells express the γδ TCR.
- γδ T cells in lymphoid organs express more diverse TCRs than
the epithelialγδ cells.
- γδ T cells do not recognize MHC-associated peptide antigens
and are not MHC restricted.
- Some γδ T cell clones recognize small phosphorylated
molecules, alkyl amines, or lipids that are commonly found in
mycobacteria and other microbes and that may be presented
by nonclassical class I MHC–like molecules.
- Other γδ T cells recognize protein or nonprotein antigens that
do not require processing or any particular type of APCs
- Many γδ T cells are triggered by microbial heat shock
proteins.
 A number of biologic activities have been ascribed to γδ T
cells, including secretion of cytokines and killing of infected
cells
- Postulated that this subset of T cells may initiate immune
responses to microbes at epithelia, before the recruitment
and activation of antigen-specific αβ T cells.
- Mice lacking γδ T cells, created by targeted disruption of the
γ or δ TCR gene, have little or no immunodeficiency and only
a modest increase in susceptibility to infections by some
intracellular bacteria.
Natural Killer T Cells
- CD56: NKT cells markers that are found on NK cells these are
The TCR α chains expressed have limited diversity
- In humans, these cells are characterized by a TCR α chain with
a V region that is encoded by a rearranged Vα24-Jα18 gene
segment, with little or no junctional diversity, associated with
a TCR β chain that utilizes one of three Vβ gene segments.
- Also called invariant NKT (iNKT) cells because of this limited
diversity, these cells are
- All NKT cell TCRs recognize lipids that are bound to class I
MHC–like molecules called CD1 molecules.
- NKT cells and other lipid antigen–specific T cells are capable
of rapidly producing cytokines, such as IL-4 and IFN-γ, after
activation, and they may help marginal zone B cells to
produce antibodies against lipid antigens.
- May mediate protective innate immune responses against
some pathogens, such as mycobacteria (which have lipid-rich
cell walls)
- iNKT cells may even regulate adaptive immune responses
primarily by secreting cytokines.
Mucosa-Associated Invariant T (MAIT) Cells
- Subset of T cells that express an invariant αβ TCR that uses a
rearranged Vα7.2-Jα33 gene segment.
- Recognize fungal and bacterial metabolites of the riboflavin
synthesis pathway, presented by a nonpolymorphic class I
MHC-like molecule called MHC class I-related protein 1
(MR1).
- Most MAIT cells are CD8+ and can be activated either by
MR1-restricted presentation of microbial riboflavin
derivatives or directly by cytokines including IL-12 and IL-18.
- Effector functions include secretion of inflammatory cytokine
such as IFN-γ and TNF and cytotoxicity against infected cells.
- Account for about 50% of all T cells in the human liver, while
iNKT cells and γδ T cells are relatively rare.
8 | CAÑETE, DNP