You are on page 1of 6

23/12/2017 Helper T Cells

Helper T Cells Index to this page

Types of Helper T Cells
Origin of Helper T Cells
Helper T cells are Th1 Cells
Th2 Cells
T lymphocytes that belong to the
Reciprocal inhibition of Th1 and Th2 cells.
CD4+ subset. Negative feedback of Th1 and Th2 cell formation
Th1 and Th2 cells have different chemokine receptors.
These cells have a number of direct functions, Chemokines
but they get their name from the help they CCR3
provide to other types of effector cells, such as CCR5
B cells and cytotoxic T lymphocytes (CTLs). Tfh Cells
The help consists of secreted cytokines that Th17 Cells
stimulate the helped cells. Summary Table

Types of Helper T Cells

Four kinds have been identified:

These participate in both cell-mediated immunity and antibody-mediated immunity. They are
essential for controlling such intracellular pathogens as viruses and certain bacteria, e.g.,
Listeria and Mycobacterium tuberculosis (the bacillus that causes TB). They provide cytokine-
mediated "help" to cytotoxic T lymphocytes — perhaps the body's most potent weapon against
intracellular pathogens.
These provide help for B cells and are essential for the production of IgE antibodies and assist in
the production of some subclasses of IgG as well. Antibodies are needed to control
extracellular pathogens (which — unlike intracellular parasites — are exposed to antibodies in
blood and other body fluids).
These also provide help to B cells enabling them to develop into antibody-secreting plasma
cells. This occurs in nests of lymphoid cells — called follicles — in the lymph nodes. The most
abundant helper T cells there are B-cell helpers called follicular helper T (Tfh) cells.
These protect surfaces (e.g., skin, lining of the intestine) against extracellular bacteria.

In addition, there is another related subset that dampens rather than promotes immune responses. These cells,
designated Treg, are discussed on another page. Link to it.

Origin of Helper T Cells

Like all T cells, Th cells arise in the thymus.
Link to drawing showing the anatomy of the lymphatic system, including the location of the thymus (52K).

When they acquire CD4, they are called pre-Th cells.

When they are presented with both
an antigen and
appropriate cytokines,
they begin to proliferate and become activated.
It is the nature of the stimulation — the type of antigen-presenting cell and cytokine(s) — that
determines which path they enter.

Discussion of how antigens are presented to T cells 1/6
23/12/2017 Helper T Cells

Th1 Cells
Th1 cells are produced when dendritic cells and pre-Th cells
form an immunological synapse in which the dendritic cell

presents antigen to the T cell's receptor for antigen

(TCR), and
secretes interleukin 12 (IL-12) as well as IFN-γ.

More on dendritic cells.

The paracrine stimulation by these cytokines causes the Th1

cells to secrete their own lymphokines:

interferon-gamma (IFN-γ) and

tumor-necrosis factor-beta (TNF-β) (also known as


stimulate macrophages to kill the bacteria they have

recruit other leukocytes to the site producing
act on B cells to promote antibody class switching.
help cytotoxic T cells (CTL) do their work and, probably, help convert some of them to memory cells.

Th2 Cells
Th2 cells are produced when antigen-presenting cells (APCs) present antigen (e.g., on parasitic helminth
worms or certain allergens) to the T cell's receptor for antigen (TCR) along with

the costimulatory molecule B7 (CD80 & 86)

the paracrine stimulants interleukin 4 (IL-4) and interleukin 2 (IL-2).

The identity of the APCs for Th2 responses is still uncertain. Some research indicates that basophils are the
APCs, but other research questions this role.

The major lymphokines secreted by Th2 cells are

interleukin 4 (IL-4). This

stimulates class-switching in B cells and promotes their synthesis of IgE antibodies.
acts as a positive-feedback device promoting more pre-Th cells to enter the Th2 pathway.
blocks the IFN-γ receptors from entering the immunological synapse on pre-Th cells thus
inhibiting them from entering the Th1 path (shown in red).
Interleukin 13 (IL-13). This also promotes the synthesis of IgE antibodies as well as recruiting and
activating basophils.
Interleukin 5 (IL-5). Attracts and activates eosinophils.

Link to graphic showing how Th2 cells stimulate B cells to mature into antibody-secreting plasma cells.

Two transcription factors have been found that play a critical role in the choice between becoming a Th1 or
a Th2 cell.

T-bet for Th1 cells 2/6
23/12/2017 Helper T Cells

GATA3 for Th2 cells

T-bet produces Th1 cells by

turning on the genes needed for Th1 function (e.g., for IFN-γ)
blocking the activity of GATA3.

Mice whose genes for T-bet have been "knocked-out" lack Th1 cells and have elevated numbers of Th2
cells (making them susceptible to such Th2-mediated disorders as asthma).

GATA3 produces Th2 cells by

turning on the genes needed for Th2 function (e.g., for IL-5)
blocking the activity of T-bet

Reciprocal inhibition of Th1 and Th2 cells.

The antigenic stimulus that sends pre-Th cells down one path or the other also sets the stage for reinforcing
the response.

A Th1 response inhibits the Th2 path in two ways:

IFN-γ (shown above in red) and IL-12 inhibit the formation of Th2 cells;
IFN-γ also inhibits class-switching in B cells.

A Th2 response inhibits the Th1 path:

IL-4 suppresses Th1 formation (shown above in red).

significance for public health: infection by helminths — common in the tropics — increases one's risk
of viral and bacterial diseases, and in laboratory mice has been shown to enhance viral infections.

Negative feedback of Th1 and Th2 cell formation

There is also evidence that late in the immune response, negative feedback mechanisms come into play to
dampen the response.

IL-4 kills (by apoptosis) the precursors of the dendritic cells that induce the Th2 path and thus further
production of IL-4.
IFN-γ may eventually turn off the Th1 response that produced it.

Th1 and Th2 cells have different chemokine receptors.

Chemokines are cytokines that are chemotactic for (attract) leukocytes. The members of one group, who
share a pair of adjacent cysteine (C) residues near their N-terminal, are designated CC chemokines.

Chemokines bind to receptors on the responding leukocyte. The receptors are transmembrane proteins with
the chemokine binding site exposed at the surface of the plasma membrane. CC chemokine receptors are
designated CCR.

With their different functions, we might expect that Th1 cells and Th2 cells would respond differently to
chemokines. And so they do.

Th1 cells express the chemokine receptor CCR5 (but not CCR3).
Th2 cells express the chemokine receptor CCR3 (but not CCR5). 3/6
23/12/2017 Helper T Cells


One chemokine that binds to CCR3 is called eotaxin. It is secreted by epithelial cells and phagocytic cells in
regions where allergic reactions are occurring.

CCR3 is found on

Th2 cells

all cells implicated in allergic responses (e.g., asthma).


CCR5 is found on

Th1 cells, especially those in the lymphoid tissue of the intestine


CCR5 also acts — along with the CD4 molecule — as a coreceptor for HIV-1, the retrovirus that causes
AIDS. This fact may explain

why destruction of the lymphoid tissue of the intestine occurs soon after HIV infection;
why certain HIV-infected men
with inherited mutations preventing the expression of CCR5 or
who produce high levels of the natural ligand for CCR5 (a chemokine designated CCL3L1,
which presumably competes with HIV for access to CCR5)
can tolerate their infection for long periods without progressing to a full-blown case of AIDS;
the collapse of cell-mediated immunity in the late stages of AIDS.

One striking illustration: an AIDS patient with leukemia was given a bone marrow transplant from a donor
whose cells expressed a nonfunctional version of CCR5. Two years later, the patient was not only cured of
his leukemia but of AIDS as well.
Another: Gene therapy in which samples of a patient's CD4+ T cells were treated in vitro so that their
CCR5 gene became nonfunctional [how it was done]. Expanded in culture and then returned to the donor,
five (of six) patients had their CD4+ T cell counts rebound.

Tfh Cells
Follicular helper T cells (Tfh) are
CD4+ helper T cells found in nests of
B cells — called follicles — in the
lymph nodes.

When exposed (in the paracortical

area of the lymph node) to

cells presenting antigen to them,

e.g., dendritic cells and
a cocktail of cytokines

they migrate into the follicles. 4/6
23/12/2017 Helper T Cells

The combined stimuli of antigen binding to their TCR and exposure to cytokines activate a transcription
factor called Bcl-6 (first identified in a B-cell lymphoma). Bcl-6 turns on a collection of genes which, among
other things, cause the Tfh cells to form an immunological synapse with those B cells expressing the antigen
fragments in class II histocompatibility molecules that match their TCR.

Several other pairs of ligands and their receptors stabilize the synapse, including the interaction between
CD28 on the Tfh cell and its ligand, B7, on the B cell [View].

These binding interactions stimulate the B cell to

undergo class switching with the synthesis of other antibody classes (except IgE);
undergo affinity maturation;
form antibody-secreting plasma cells and
memory B cells.

This intense activity within the follicle forms a germinal center.

It is not yet certain whether Tfh cells represent a distinct class of Th cells or are simply a further stage in the
maturation of Th1, or Th2, or Th17 cells.

Th17 Cells
Th17 cells are a recently-identified subset of CD4+ T helper cells. They are found at the interfaces between
the external environment and the internal environment, e.g., skin and lining of the GI tract.

They probably start out like other "naive" Th cells, but when exposed to

cells presenting antigen to them, e.g., dendritic cells

several cytokines notably
transforming growth factor-beta TGF-β, and

they enter a pathway distinct from that of Th1, Th2, and Tfh cells. The combined stimuli of

antigen binding to the TCR and

exposure to the cytokines

activate a nuclear retinoid receptor designated RORγt. This is a transcription factor that turns on a collection
of genes which, among other things, leads to

the synthesis and secretion of IL-17 (giving the cells their name);
increased synthesis of the plasma membrane receptor for the interleukin IL-23. Interaction of IL-23
(perhaps secreted from nearby dendritic cells) with the receptor drives the rapid proliferation of the
Th17 cells.

Situated in the skin and the lining of the GI tract, Th17 cells are positioned to attack fungi and bacteria at
those locations. They do this by secreting defensins and recruiting scavenging cells, especially neutrophils,
to the site. The result: clearing away of the invaders with accompanying inflammation.

But inflammation is a double-edged sword. So it is not surprising that Th17 cells have been implicated as
potent effectors of such damaging inflammatory disorders as

Crohn's disease (an inflammation of the small intestine);

ulcerative colitis (inflammation of the large intestine);
psoriasis (inflammation of the skin);
an animal model (in mice) of multiple sclerosis;
rheumatoid arthritis. 5/6
23/12/2017 Helper T Cells

Summary Table
Cytokine Effector Main Target Effector Pathological
Type Transcription
Stimulus Cytokine(s) Cells Targets/Functions Effects
IFN-γ & Macrophages,
Th1 IL-12 & IL-2 T-bet Intracellular pathogens cell-mediated
TNF-β dendritic cells
Eosinophils, Asthma and
IL-4, IL-5
Th2 IL-4 GATA3 basophils, B Various helminths IgE-mediated
& IL-13
cells allergies
Class Switch
IL-21 &
Recombination and Autoimmune
Tfh IL-2 & others Bcl-6 either IL-4 B cells
Affinity Maturation of diseases?
or IFN-γ
TGF-β plus
Extracellular bacteria
IL-6 IL-17, IL- Autoimmune
Th17 RORγt Neutrophils and fungi
Inhibited by 22 & IL-23 diseases
mediates inflammation
retinoic acid
TGF-β minus
IL-6 all the other
IL-10 & Immunosuppression;
pTreg Stimulated by Foxp3 types of T None?
TGF-β anti-inflammatory
retinoic acid cells
and IL-2

Welcome&Next Search

10 December 2015 6/6