|Index to this page|
Helper T cells are
These cells have a number of direct functions, but they get their name from the help they provide to other types of effector cells, such as B cells and cytotoxic T lymphocytes (CTLs). The help consists of secreted cytokines that stimulate the helped 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 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.
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
- 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|
- 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 lymphotoxin)
- stimulate macrophages to kill the bacteria they have engulfed;
- recruit other leukocytes to the site producing inflammation;
- 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.
- 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.
GATA3 produces Th2 cells by
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.
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.
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).
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
all cells implicated in allergic responses (e.g., asthma).
CCR5 is found on
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
- 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.|
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
they migrate into the follicles.
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 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
- 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.
|Effector Cytokine(s)||Main Target Cells||Effector Targets/Functions||Pathological Effects|
|Th1||IL-12 & IL-2||T-bet||IFN-γ & TNF-β||Macrophages, dendritic cells||Intracellular pathogens||Autoimmunity;
|Th2||IL-4||GATA3||IL-4, IL-5 & IL-13||Eosinophils, basophils, B cells||Various helminths||Asthma and IgE-mediated allergies|
|Tfh||IL-2 & others||Bcl-6||IL-21 & either IL-4 or IFN-γ||B cells||Class Switch Recombination and Affinity Maturation of antibodies||Autoimmune diseases?|
|Th17||TGF-β plus IL-6
Inhibited by retinoic acid
|RORγt||IL-17, IL-22 & IL-23||Neutrophils||Extracellular bacteria and fungi
|pTreg||TGF-β minus IL-6
Stimulated by retinoic acid and IL-2
|Foxp3||IL-10 & TGF-β||all the other types of T cells||Immunosuppression; anti-inflammatory||None?|
10 December 2015