Helper T Cells
Helper T cells are
Types of Helper T
Cells
There are two distinct kinds:
- Th1
- Th2
- These provide help
for B cells and, in so doing, are essential for antibody-mediated immunity. Antibodies are
needed to control extracellular pathogens (which — unlike
intracellular parasites — are exposed to antibodies in blood and other
body fluids).
Origin of Helper T
Cells
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 that determines which path they enter: the path leading to Th1
cells or the path leading to Th2 cells.
The antigen-presenting cells (APCs) are called dendritic cells (DCs).
There are several subsets of them: some produced by monocytes
and others derived from a progenitor
cell that gives rise to both them and monocytes.
Dendritic cells
(Dendritic cells can also present intact antigen directly to B
cells. In this case, the engulfed antigen is not degraded in
lysosomes but is returned to the cell surface for presentation to B cells
bearing BCRs
of the appropriate specificity.)
There are at least two kinds of dendritic cell that present antigens to T
cells:
Th1 Cells
when DC1-type 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);
- secretes interleukin 12 (IL-12).
The paracrine
stimulation by IL-12 activates (through JAK-STAT
pathways) 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
Th2 cells are produced when DC2-type dendritic cells present antigen to the
T cell's receptor for antigen (TCR) and, presumably, one or more paracrine
stimulants. The identity of the cytokine(s) is still uncertain (indicated by a
? in the figure).
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 5 (IL-5).
Attracts and activates eosinophils.
- Interleukin 10 (IL-10).
Inhibits IL-12 production by DCs thus inhibiting pre-Th cells from
entering the Th1 pathway.
- Interleukin 13 (IL-13).
This also promotes the synthesis of IgE antibodies.
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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 CD8+ Cytotoxic
T Cells (CTL) also come in two subsets:
- Tc1 that,
like Th1 cells, secrete IFN-γ and
- Tc2 that,
like Th2 cells, secrete IL-4.
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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 and IL-10
suppress Th1 formation (shown above in red).
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 the precursors
of the DC2 cells (by apoptosis) thus inhibiting the Th2 path and
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.
Because they are chemotactic cytokines, chemokines are designated
by the initials CC.
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. 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
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 in 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;
14 January 2006
