K. Takahashi, et al.,
"Induction of pluripotent
stem cells from
adult human fibroblasts by defined
factors," Cell, 131(5):
861-72, 30 November 2007. [Kyoto
U., Japan; CREST, Kawaguchi, Japan;
Gladstone Inst. Cardio. Dis., San
Francisco, CA] *243MG
96
1
2
K. Takahashi, Y. Shinya, "Induction of
pluripotent stem cells from mouse
embryonic and adult fibroblast cultures
by defined factors," Cell,
126(4): 663-76, 25 August 2006. [Kyoto
U., Japan; CREST, Kawaguchi, Japan]
*080VN
76
†
3
The ENCODE Project Consortium (
E. Birney, et al.),
"Identification and analysis of
functional elements in 1% of the human
genome by the ENCODE pilot project,"
Nature, 447(7146): 799-816, 14
June 2007. [80 institutions worldwide]
*178FV
61
2
4
M. Wernig, et al., "In
vitro reprogramming of fibroblasts
into a pluripotent ES-cell-like state,"
Nature, 448(7151): 318-24, 19
July 2007. [5 U.S. institutions] *191GC
61
4
5
K. Okita, T. Ichisaka, S. Yamanaka,
"Generation of germline-competent
induced pluripotent stem cells,"
Nature, 448(7151): 313-7, 19
July 2007. [Kyoto U., Japan; Japan Sci.
Tech. Agency, Kawaguchi] *191GC
59
3
6
I.I. Ivanov, et al., "The
orphan nuclear receptor ROR?t directs
the differentiation program of
proinflammatory IL-17+ T
helper cells," Cell, 126(6):
1121-33, 22 September 2006. [Howard
Hughes Med. Inst., New York U., NY;
Schering-Plough BioPharma, Palo Alto,
CA] *089RF
54
9
7
A. Barski, et al.,
"High-resolution profiling of histone
methylations in the human genome,"
Cell, 129(4): 823-37, 18 May
2007. [NHLBI, NIH, Bethesda, MD; U.
Calif., Los Angeles] *172FA
51
†
8
T. Korn, et al., "IL-21
initiates an alternative pathway to
induce proinflammatory TH17
cells," Nature, 448(7152):
484-7, 26 July 2007. [Harvard Med.
Sch., Boston, MA] *193VG
44
†
9
L. Zhou, et al., "IL-6
programs TH-17 cell
differentiation by promoting sequential
engagement of the IL-21 and IL-23
pathways," Nature Immunol.,
8(9): 967-74, September 2007. [NYU Sch.
Med., and Howard Hughes Med. Inst., NY;
NHLBI, Bethesda, MD] *202QN
38
†
10
R. Nurieva, et al., "Essential
autocrine regulation by IL-21 in the
generation of inflammatory T cells,"
Nature, 448(7152): 480-3, 26
July 2007. [M.D. Anderson Cancer Ctr.,
Houston, TX; Inst. Syst. Biol.,
Seattle, WA; NIH, NIEHS, Research
Triangle Park, NC] *193VG
A single topic occupying four of the Top Ten places (with a fifth
hovering just outside at #12) indicates something rather special afoot.
That something is the scramble to understand a relatively recently
identified component of the immune system, the TH17 helper cell,
which is specially adapted to fighting bacterial and fungal diseases. It is
also implicated in autoimmune disorders such as inflammatory bowel disease,
psoriasis, and rheumatoid
arthritis.
For the past 35 years or so immunologists have considered two basic kinds
of T helper cells in the immune system. TH1 and TH2
cells are classes of white blood cell that are not themselves capable of
destroying invading pathogens. Instead, they are activated by exposure to
antigens and are the core of the immune system's memory. T helper cells
recruit and activate the cytotoxic cells, also known as T killer cells,
that actively dispatch the pathogens. During their differentiation from
naive T cells, TH1 and TH2 cells produce cytokine
trigger molecules that prod other naive cells down the TH1 or
TH2 development pathways, an autocrine response that can rapidly
boost the number of T helper cells sensitive to a particular antigen.
TH17 cells were first
described as having an origin distinct from
TH1 and TH2 lineages, triggered by the cytokines
IL-6 and TGF-ß, but these did not seem to be autocrine messengers
that could amplify the production of TH17 cells.
Starting the current ball rolling, and highest in the Top Ten at #6, Dan
Littman's group at the Howard Hughes Medical Institute and the New York
University School of Medicine showed that a key upstream element is
provided by the transcription factor known as ROR?t. This factor switches
on the genes that encode IL-17 in naive T cells, and IL-17 is necessary for
naive cells to respond to IL-6 and TGF-ß. Mice that lacked the
ROR?t gene did not suffer certain autoimmune
diseases and lacked fully competent TH17 cells. Littman's
group noted that, given TH17's role in autoimmune diseases,
this new function for ROR?t highlighted "its potential as a therapeutic
target in inflammatory diseases."
Next come the two papers at #8 and #10, published back-to-back in
Nature. Vijay Kuchroo's group at Harvard Medical School (#8) and
Chen Dong and Roza Nurieva at the M.D. Anderson Cancer Center and their
group (#10) both showed that yet another interleukin, IL-21, was produced
by differentiating TH17 cells and, more importantly, triggered
naive T cells to become TH17 cells. Thus IL-21 was the autocrine
cytokine that people had been looking for, both necessary and sufficient to
produce TH17 cells. Sandwiched between those two papers, at #9,
is another report from Dan Littman's group that also identified IL-21 as
able to cause differentiation of TH17 cells. IL-21 too was thus
a target for therapy.
It therefore seems that IL-6 and TGF-ß cause the expression of ROR?t,
which enables T cells to respond to IL-23, a third cytokine associated with
TH17 differentiation. IL-6 also triggers the production of
IL-21, and IL-21 is enough to trigger the differentiation of naive cells,
even in the absence of IL-6.
Complicating this already complex picture still further are the results
reported in the paper at #12. Federica Sallusto and Eva Acosta-Rodriguez
and their group at the Institute for Research in Biomedicine in Bellinzona,
Switzerland, looked not at mice but at the differentiation of human
TH17 cells (E.V. Acosta-Rodriguez, et al., Nature
Immunology, 8[9]: 942-9, September 2007; 37 citations this period).
Perhaps surprisingly, they found that TGF-ß is not needed for the
production of IL-17 in human cells. Indeed, TGF-ß can inhibit IL-17.
And while IL-6 alone is not a very good stimulus for TH17
differentiation, it is much more effective in combination with IL-1.
Furthermore, there seems to be a great deal of variation in the amount of
IL-17 produced by different donors. If this is linked to the production of
TH17 cells, then the detailed influence of genetic factors on
autoimmune diseases is likely to be fertile ground for further
investigation.
Why the differences between mice and men? There are no ready answers, but
one possibility is that it is much more difficult for researchers to be
certain that they are dealing with truly naive T cells in human subjects.
In addition, it may be that T helper cells are not quite so set in their
ways as has been presumed. Maybe the various lineages can somehow be
converted from one type to another, which might allow more flexibility in
the response to an immune challenge. There is also the likelihood that some
of the genes involved may be the subject of epigenetic modifications, which
would further complicate the picture.
Dr. Jeremy Cherfas is Science Writer at Bioversity International in
Rome, Italy.
Keywords: T helper cells, Th-17, IL-6, immune response, TGF-beta, IL-17,
Dan Littman, Frederica Sallusto, Eva Acosta-Rogriguez.