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:
- Th1
- Th2
- These provide help for B cells and are essential for the production of IgE antibodies and perhaps assist in the production of other classes as well. Antibodies are needed to control extracellular pathogens (which — unlike intracellular parasites — are exposed to antibodies in blood and other body fluids).
- Tfh
- 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.
- Th17
- 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.
- When they acquire CD4, they are called pre-Th cells.
- When they are presented with both
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.
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 interleukin 18 (IL-18) and IFN-γ (not shown).
The paracrine stimulation by these cytokines causes the Th1 cells to secrete their own lymphokines:
- tumor-necrosis factor-beta (TNF-β) (also known as lymphotoxin) and
- interferon-gamma (IFN-γ)
These
- stimulate macrophages to kill the bacteria they have engulfed;
- recruit other leukocytes to the site producing inflammation.
Th2 cells are produced when basophils present antigen to the T cell's receptor for antigen (TCR) along with
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.
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
- GATA-3 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 GATA-3.
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).
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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).
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).
CCR3
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
- Th1 cells, especially those in the lymphoid tissue of the intestine
- macrophages
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). CCL3L1 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 did not express CCR5. Two years later, the patient was not only cured of his leukemia but of AIDS as well. |
Tfh cells are a recently-identified subset of CD4+ helper T cells. They are found in nests of B cells — called follicles — in the lymph nodes.
They probably start out like other "naive" Th cells, but when exposed to
they enter a pathway that appears to be distinct from that of Th1 and Th2 cells. The combined stimuli of
- antigen binding to the TCR and
- exposure to IL-6 and IL-21
activate a transcription factor called Bcl6 (first identified in a B-cell lymphoma). Bcl6 turns on a collection of genes which, among other things, cause the Tfh cells to collect in the follicles where they stimulate B cells to
Th17 cells are another 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
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 TGF-β and IL-21
activate a nuclear receptor designated ROR. 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);
- the synthesis of a 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 autoimmune 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.
1 November 2009
