Trio of Papers Elucidates Development of Th17 Cells

Trio of Papers Elucidates Development of Th17 Cells

by Jeremy Cherfas

WHAT'S HOT IN BIOLOGY
Rank	Paper	Citations This Period (Mar-Apr 07)	Rank Last Period (Jan-Feb 07)
1	D. Altshuler, et al. (Int.’l HapMap Consortium), "A haplotype map of the human genome," Nature, 437(7063): 1299-1320, 27 October 2005. [63 institutions worldwide] *977UQ	59	1
2	E. Bettelli, et al., "Reciprocal developmental pathways for the generation of pathogenic effector T_H17 and regulatory T cells," Nature, 441(7090): 235-8, 11 May 2006. [Harvard Med. Sch., Boston, MA] *040YP	30	†
3	T. Matsumoto, et al. (Int.’l Rice Genome Sequencing Project), "The map-based sequence of the rice genome," Nature, 436(7052): 793-800, 11 August 2005. [32 institutions worldwide] *953XG	27	†
4	M. Veldhoen, et al., "TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells," Immunity, 24(2): 179-89, February 2006. [MRC Natl. Inst. Med. Res., London, U.K.; Howard Hughes Med. Inst., U. Calif., San Francisco] *014KN	25	†
5	R.L. Levine, et al., "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis," Cancer Cell, 7(4): 387-97, April 2005. [7 U.S. and European institutions] *921CL	24	†
6	D.K. Pokholok, et al., "Genome-wide map of nucleosome acetylation and methylation in yeast," Cell, 122(4): 517-27, 26 August 2005. [Whitehead Inst., Cambridge, MA; MIT, Cambridge] *959YI	24	†
7	S.B. Long, E.B. Campbell, R. MacKinnon, *"Crystal structure of a mammalian voltage-dependent Shaker* family K⁺ channel,"** Science, 309(5736): 897-903, 5 August 2005. [Howard Hughes Med. Inst., Rockefeller U., New York, NY] *953SS	23	†
8	T.S. Mikkelsen, et al. (The Chimpanzee Seq. and Analysis Consort.), "Initial sequence of the chimpanzee genome and comparison with the human genome," Nature, 437(7055): 69-87, 1 September 2005. [23 institutions worldwide] *960AC	22	†
9	L.E. Harrington, et al., "Interleukin 17-producing CD4⁺ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages," Nature Immunology, 6(11): 1123-32, November 2005. [U. Alabama, Birmingham; Howard Hughes Med. Inst., Washington U. Sch. Med., St. Louis, MO] *977WD	22	†
10	J.D. Fontenot, et al., "A function for interleukin 2 in Foxp3-expressing regulatory T cells," Nature Immunology, 6(11): 1142-51, November 2005. [Rockefeller U., New York, NY; NCI, NIH, Bethesda, MD; U. Birmingham, U.K.] *977WD	22	†
SOURCE: Thomson Scientific's Hot Papers Database. Read the Legend.

ew things about the detailed workings of the immune system are simple for a non-specialist, although there used to be one: T cells, the workhorses of the immune system, included a subset known as T helper cells, and these came in two distinct flavors. Th1 cells produce interferon-gamma and are responsible for getting rid of pathogens like bacteria and viruses within the host's cells. Th2 cells produce interleukin-4 and deal with extra-cellular problems, such as parasitic worms. Then there are regulatory T (Treg) cells, which generally regulate the immune response and keep it from getting out of hand. Imbalances among them were thought to underly different kinds of disease. Excess Th1 seemed to be associated with autoimmune diseases such as multiple sclerosis. Th2 was linked to allergies and asthma. Alas, that simple (not to say simplistic) understanding has been rent asunder by the discovery of a new player: Th17, so called because it produces interleukin-17.

Three papers in the Top Ten discuss Th17. At #2 is a paper from Vijay Kuchroo's team at Harvard Medical School which shows how naive T cells are turned into either Th17 cells or Treg cells depending on the exact conditions at the time that T-cell differentiation is triggered. At #4, Brigitta Stockinger's group at the Medical Research Council's Division of Molecular Immunology in London, has similar, earlier results on the formation of Th17 and Treg cells. And at #9, an earlier paper yet from Laurie Harrington and the group at Casey Weaver's laboratory at the University of Alabama, sets out the stimuli that turn naive T cells into Th17 cells.

The three papers each come to roughly the same conclusions (albeit in more detail as time progresses) using very different approaches that by their diversity serve to underline the robustness of the results. The picture that emerges is one of exquisite balance. Th17 cells represent a distinct independent line that is not a branch from either Th1 or Th2 lines. Indeed, the outputs of Th1 and Th2—interferon-g and IL-4—suppress the differentiation of Th17 cells from naive T cells. Normally, cells that have been infected produce proinflammatory signals like IL-12 and IL-18, which then promote the development of Th1 cells. However, in the presence of TGF-β1, these same signals cause naive T cells to become Th17 cells. Another interleukin, IL-23, is an essential component of the system, but on its own does not trigger the differentiation of Th17 cells. It is, however, necessary for the survival and proliferation of Th17 cells.

That picture is correct at least in outline, although there are several other feedback loops, positive and negative, that determine the relative balance among Th1, Th2, Th17 and Treg. And it is that balance, or rather the lack of it, that is almost certainly behind the giddy citation rates. The role of T helper cells in autoimmune and inflammatory diseases—among them rheumatoid arthritis, lupus, asthma, and graft rejection—means that any deeper understanding of how these cells are controlled holds out hope of restoring control in cases of disease. Bettelli et al. (#2) show that mice overexpressing TGF-β1 have more Th17 cells and more severe autoimmune disease. They also had fewer Treg cells. But one cannot simply suppress IL-23 and TGF-β1, because the host will then be unable to fight off extracellular pathogens. Therapies are clearly within the grasp of researchers, although it will be some time before all the obstacles have been overcome.

Another recent study (J.L. Langowski, et al., Nature, 442[7101]: 461-5, 2006) says that IL-23 and IL-17 are increased in human cancers and that a lack of IL-23 in mice predisposed to develop tumors reduces the number of tumors. It has long been theorized that there is a link between chronic inflammation and increased incidence of malignancy. IL-23 seems to provide a clear link, and it may be that Th17 and its controls are instrumental in the failure of the body to recognize and infiltrate tumors.

Dr. Jeremy Cherfas is Science Writer at Bioversity International, Rome, Italy.


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Science Watch^®, September/October 2007, Vol. 18, No. 5
Citing URL: http://www.sciencewatch.com/sept-oct2007/sw_sept-oct2007_page8.htm