Mysterious gdT Cells Promote Wound Repair

By Jason Socrates Bardi

[He took] from thence a Rib, with cordial spirits warme, And Life-blood streaming fresh; wide was the wound, But suddenly with flesh fill'd up & heal'd

———John Milton, Paradise Lost, 1667

At the roots of some of the most symptomatically unrelated chronic human health problems like wheezing, itchy skin, and diarrhea are biologically similar inflammatory diseases of the "epithelial" outermost layers of the lung, gut, and skin.

Diseases like asthma, psoriasis, and ulcerative colitis are all caused by adverse inflammation of their respective epithelial tissues, and the key to treating some of these diseases may come from understanding a single type of immune cell that resides mainly in these epithelial tissues—the heretofore mysterious gd T cell (pronounced "gamma–delta").

Scientists had for years postulated various biological roles for the cells, and many researchers had sought to determine how they might be involved in diseases. Until now these studies only deepened the mystery of the gd T cell. Recently, the first major biological role of this cell was identified by scientists at The Scripps Research Institute (TSRI), and the story goes that these cells play a major role in promoting wound repair.

"Very little has been known about the function of these cells until now," says TSRI investigator Wendy Havran, who is an associate professor in the Department of Immunology at TSRI and has been studying gd T cells for several years. She led the effort that detected this novel function of gd T cells.

A Cell of Known Origin but Unknown Function

What had been learned of gd T cells in the nearly two decades since their initial discovery was that they arise early in fetal development in the thymus. From there, they migrate to epithelial tissues—the thin layer of cells that makes up the outermost layers of skin and lines organs like the intestines and lungs.

Unlike the canonical T cells of the immune system, the "white blood" ab T cells in blood, most gd T cells do not circulate through the bloodstream. Instead, they are the major T cell component of the skin, lung, and intestine, where they take up residence and monitor the neighboring epithelial cells for damage and disease. Some gd T cells, however, do circulate in the bloodstream and may carry out completely different biological functions than the skin gd T cells.

Though gd T cells are the first T cells the thymus produces, this organ nearly shuts off production of them later in development. Throughout life, the body maintains its population of gd T cells "on-site," allowing them to divide as needed.

In the epidermis where the gd T cells are concentrated, numbering half a thousand cells per square centimeter, they have a spiny, stretched-out, finger-like shape that contacts as many skin cells as possible.

Also unlike other T cells in the body, which display a wide diversity of receptors that recognize a wide diversity of antigens—the molecular components of various pathogenic invaders—the gd T cells in the skin seem to have little, if any, diversity and display a uniform receptor and recognize only a single antigen.

This recognition event appears to be crucial for mediating wound healing.

Activated by Keratinocytes

"When wounds heal, the epithelial cells in the skin have to proliferate and fill in the wounds," says Havran. She found in a recent study with Research Associate Julie Jameson that gd T cells help this proliferation.

The study, "A Role for Skin gd T cells in Wound Repair" by Julie Jameson, Karen Ugarte, Nicole Chen, Pia Yachi, Elaine Fuchs, Richard Boismenu, and Wendy L. Havran was published in the April 26, 2002 issue of the journal Science. It showed that when skin is cut or damaged, keratinocytes, which are the major type of epithelial cell in the epidermis, are able to faster re-epithelialize tissue that has been wounded if they can get help from the gd T cells.

Havran and Jameson postulate that the keratinocytes, sensing the damage, release an antigen that is recognized by the gd T cells, which then become activated. Once activated, the gd T cells undergo a morphological change and become little round factories. These begin mass-producing a growth factor that binds to keratinocytes and other epithelial cells, helping them proliferate and leading to the closure of the wound. The gd T cells also proliferate, multiplying to increase the response to the wound.


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Wendy Havran, associate professor in the Department of Immunology at TSRI, has been studying gd T cells for several years. Photo by Kevin Fung.





Research Associate Julie Jameson was first author on the study. Photo by Kevin Fung.