The first, most basic career choice made by precursors of the adaptive arm of the immune system is whether to adopt the B-cell or T-cell fate. Both originate from stem cells in the bone marrow, but B cells mature there while T cells migrate to the thymus gland, which governs their development.
"The recognition and destruction of invading pathogens by T lymphocytes is essential to the ability of humans to resist disease," said Wiest. "T cells recognize these invaders by means of a surface structure called the T-cell antigen receptor complex, or TCR."
Two distinct lineages of T cells utilize distinct types of TCR complexes. One lineage employs pairs of TCR proteins termed alpha-beta while the other uses the TCR gamma-delta pair of proteins. The alpha-beta and gamma-delta pairs of proteins represent the "eyes" of the TCR complex and enable these distinct types of T cells make unique contributions to our ability to resist disease.
The more numerous T cells of the alpha-beta lineage provide protection against infectious diseases either by helping B cells generate antibodies against external agents (helper T cells) or by directly attacking and destroying cells infected by foreign invaders (killer T cells). Gamma-delta T cells migrate from the thymus to epithelial tissues such as skin and the linings of the lung. While their precise role remains poorly understood, they perform vital protective functions. Certain lung infections easily cleared from normal laboratory mice are a death sentence for those lacking gamma-delta T cells.
Despite their clear importance in resisting disease, the processes controlling the generation of gamma-delta T cells have remained mysterious until recently. As Robert Frost put it, Wiest pointed out:
"Two roads diverged in a wood, and I--
I took the one less traveled by,
And that has made all the difference."
"Gamma-delta T cells represent the road less traveled," Wiest said. "However, the role of the TCR in determining lineage is controversial, particularly whether different forms of TCR predetermine a cell's fate and whether or not their signals control the choice."
In the new study, Wiest and his colleagues use several models to manipulate the signaling strength of the gamma-delta TCR. A strong signal, produced in the presence of a specific binding substance, or ligand, directs immature T cells almost exclusively to the gamma-delta lineage. However, weakening the signal promotes alpha-beta lineage development.
"The signal strength determines the level of expression of early growth response (Egr) proteins, with cells choosing the gamma-delta lineage expressing far greater quantities of Egr proteins than those adopting the alpha-beta lineage," explained Wiest. "Egr proteins regulate which cellular genes are turned on or off so we think that high-level expression of Egr proteins instructs cells to express the set of cellular genes necessary to become a gamma-delta T cell."
Understanding the development of critical components of the immune system can lead to scientific and medical advances in stimulating desirable immune responses and halting unwanted ones.
"Although their precise function is still unclear, delta-gamma T cells seem to form the first line of response against external disease-causing agents, including bacterial infections, tissue damage and stress," Wiest said. "Laboratory mice unable to make delta-gamma T cells heal skin injuries more slowly.
"Immune surveillance, the body mechanism that detects potential cancers and destroys them before their presence is evident to us, may be one function of the delta-gamma lineage, since gamma-delta T cells appear to be particularly adept at combating skin cancers," Wiest added.
In addition to Wiest and Kappes, Fox Chase co-authors of the new Immunity paper include postdoctoral fellow Mariëlle C. Haks, Ph.D. (currently at Leiden University Medical Center in The Netherlands), graduate student Juliette Lefebvre, postdoctoral associate Jens Peter H. Lauritsen, Ph.D., research associate Michael Carleton, Ph.D. (now at Rosetta Inpharmatics in Seattle), and scientific technician Michele R. Rhodes, along with Toru Miyazaki, M.D., Ph.D., of the University of Texas Southwestern Medical Center's Center for Immunology in Dallas.
Grants from the National Institutes of Health and an appropriation from the Commonwealth of Pennsylvania helped support this work along with a Fox Chase Cancer Center Board of Directors Postdoctoral Fellowship and a stipend from the Netherlands Organization of Scientific Research for Haks.
Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation's first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at www.fccc.edu or call 1-888-FOX CHASE.
Journal
Immunity