Science Writer

In recent years, type 1 helper T cells, which play a role in fighting intracellular bacterial and viral infections, and type 2 helper T cells, which are more active against parasites, have been joined by a third sibling: interleukin-17 producing or TH17 T cells.

Distinct from the major types 1 and 2, those cells appear to protect against bacteria and viruses at the skin surface. They also play a role in autoimmune diseases like multiple sclerosis, arthritis and inflammatory bowel disease. Two papers in the January 2008 and December 2007 issues of Nature Immunology investigated how and why interleukin-17 producing cells contribute to autoimmune disease.

In a paper published online Dec. 23, 2007, and titled "Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice," researchers from the University of Alabama at Birmingham describe a new mechanism by which IL-17 does its damage when it is produced by TH17-type cells.

IL-17 induces tissue damage in part because it is a strong pro-inflammatory molecule. Studies also have shown that blocking IL-17 signaling decreases autoantibodies. In their paper, the scientists show how: by promoting the formation of germinal centers - specialized structures within lymph tissue where antibody-producing B cells can interact with antigen-producing T cells and rapidly divide - and affecting chemokines that regulate them.

In the study, the scientists showed that disrupting IL-17 signaling significantly reduced the number of B cells clustered in germinal centers, partly through its effects on two upstream proteins that regulate g-protein-coupled receptors, rgs13 and rgs16. The authors suggested that targeting either the rgs proteins or the germinal centers might be a way to prevent the formation of autoantibodies.

The second paper, which appeared online in the December 2007 issue of Nature Immunology, deals with how IL-17 production itself is regulated and what makes TH17-type cells go bad in the first place. It is titled "TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology" and its authors hail from Schering-Plough Biopharma in Palo Alto, Calif. The paper was one of four published in Nature Immunology last month investigating the interplay of different interleukins, mainly IL-27 and IL-10, in the regulation of T cells.

In their paper, the Schering-Plough scientists investigated how memory T cells start producing IL-17, and which factors determine whether those cells will become autoimmunity culprits or not.

The authors stimulated T cells with different cocktails of interleukins and growth factors, and found that the combination made all the difference. "Cells stimulated with TGF-beta plus IL-6 were present in the spleen as well as the central nervous system, but they failed to upregulate the proinflammatory chemokines crucial for central nervous system inflammation. In addition, these cells produced IL-10, which has potent anti-inflammatory activities," they wrote.

The problem cells developed when memory T cells were stimulated with the interleukin IL-23. Such stimulation, the authors wrote, "promoted expression of IL-17 and proinflammatory chemokines but not IL-10," leading to autoimmune reactions in the animal equivalent of multiple sclerosis. The researchers concluded that "TGF-beta and IL-6 drive' initial lineage commitment but also 'restrain' the pathogenic potential of TH-17 cells."

Evaluating the paper on the website Faculty of 1000, Jay Berzofsky from the National Cancer Institute wrote that "This study provides an explanation for the paradoxical role of transforming growth factor-beta (TGF-beta) in autoimmune disease, in which it has been found that TGF-beta is necessary for induction of pathogenic Th17 cells producing IL-17, but that TGF-beta also ameliorates disease. . . . Understanding what regulates the switch from a benign to a pathogenic T cell may be critical for devising novel treatments for multiple sclerosis and other related autoimmune diseases."