Sorting out the Triggers,
Differentiation, and Roles of TH-17
by Jeremy Cherfas
Oh, the drama that hides behind Science Watch's inexorable
grinding of data. Making its first Top Ten appearance at
#8—the only newcomer in fact—is a paper from Federica
Sallusto's group at the Institute for Research in Biomedicine in
Switzerland. This occasion is its last opportunity to appear,
because the Hot Papers lists are based on citations over the
preceding two years, and this paper, dating back to June 2007, will
henceforth become too "old" for further eligibility. So why now?
Why the sudden late spurt?
Probably because just outside the Top 10 are a couple of papers,
including another from Sallusto and colleagues, that depend on, and
cite, #8. The big problem is that while these papers delve deeper
into the story, they actually make it more complicated. All are
about T helper cells. When a "naive" T cell is exposed to antigens
(usually from an infection) it differentiates into T helper cells,
which secrete various compounds that fight the infection directly
and summon other cells of the immune system to help.
Institute for Research in
For a long time, there were believed to be only two kinds of T
helper cell. In the
2009 issue of Science Watch from
Reuters, this column discussed a set of papers that had
crashed the Biology Top Ten and that dealt with a new kind of
immune memory cell, the TH-17 cell. It is called
TH-17 because it produces interleukin-17 (IL-17), and
had been linked to immune defense and autoimmune diseases.
Complicating that account was the Sallusto paper, then at #12, now
reappearing at #13 (E.V. Acosta-Rodriguez, et al.,
Nature Immunol., 8: 942-9, September 2007; 31 citations
this period, 206 overall). This report showed that the essential
triggers and pathways leading to the differentiation of
TH-17 cells in humans are in many respects different
from those in mice. A neighboring paper, from a team led by Rene de
Waal Malefeyt, of Schering-Plough Biopharma in Palo Alto,
California, showed likewise that the development of
TH-17 cells is fundamentally different in humans and
mice. That paper was originally not as highly cited, but now shows
up just above Sallusto at #12 (N.J. Wilson, et al.,
Nature Immunol., 8: 965-7, 2007; 31 citations this
period, 224 overall).
To deal first with the Sallusto paper at #8, one of the crucial
points was that infection with the fungus Candida albicans
specifically triggered TH-17 cells, rather than either
of the two previously known kinds of T helper cells. Why this
should be so remains a mystery, although the authors speculate that
it could have something to do with the tissue in which the
infection occurs. This gets a boost from de Waal Malefyt's team.
They looked at psoriasis sufferers, and discovered that cells from
psoriasis lesions were enriched in TH-17 cells. From
this and other evidence it seems possible that TH-17
cells exist largely to deal with infections affecting the skin.
As for the differentiation of TH-17 cells, one of the
crucial differences between mice and men is that in mice,
transforming growth factor ß (TGF-ß)
is absolutely crucial for the development of TH-17
cells, while in men (and women) it is not needed. In fact, Sallusto
and de Waal Malefyt agree that TGF-ß inhibits the
production of IL-17. They also agree that IL-1, especially in
combination with IL-6, is a potent trigger for the production of
TH-17 cells. They disagree, however, on some of the
other triggers–for example, IL-23. Sallusto et al.
find that IL-23 is not very effective at inducing TH-17
cells. By contrast, de Waal Malefyt's group find that IL-23 is a
potent inducer of TH-17 cells. For Sallusto, IL-23 in
combination with IL-1 is a better trigger than IL-1 alone. For de
Waal Malefyt, IL-1 is as potent alone as it is in combination with
What might eventually help to make sense of these disagreements is
the observation that cells from different donors vary
markedly—up to 50-fold—in the amount of IL-17 they
produce. There is some evidence that genetic and epigenetic factors
can influence IL-17 production, and it could be that the
differences between the two teams are the result of different donor
populations. Another possibility is that the human T cells being
studied are not, in fact, completely naive. Mice can be subjected
to a variety of experimental procedures to ensure that their T
cells have not been exposed to any antigens. Cells isolated from
human donors might already have been triggered to start
These mysteries will doubtless be solved eventually. And as more
and more becomes known about TH-17 cells, their role is
being investigated in everything from the bone loss associated with
severe periodontal disease to the inflammations of the gut that
characterize Crohn's disease. It is fitting, therefore, that some
of the pioneering papers had their moment in the limelight before
they grew too old.
Dr. Jeremy Cherfas is Science Writer at Bioversity
International in Rome, Italy.
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