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.

In the study, Havran and Jameson compared in vivo knockout models, which lack gd T cells, to normal models. Both types of models received identical wounds to gauge the effect of the presence of the cell type on wound closure.

"When gd T cells are missing, you see a delay in wound repair," says Havran.

The skin still has the ability to close the wound eventually, though, because fibroblast cells in the connective tissue below the epidermis can step up, produce growth factor, and eventually heal the wound.

"It's a timing issue," says Jameson, who was the lead author on the latest study. "Without the gd T cells, wounds don't heal as rapidly because they don't have the rapid producers [of keratinocyte growth factor] right there."

Solving the mystery of what the gd T cells are doing has not given Havran and Jameson all the answers, however. They know that the gd T cells recognize an antigen the keratinocytes produce, but "we'd really like to know what that antigen is," says Jameson.

They would also like to elucidate the mechanism whereby the antigen is recognized and this signal is transduced within the gd T cell to initiate the morphological change that starts the production of the keratinocyte growth factor.

Havran is also interested in determining the conserved function for all epithelial resident gd T cells. She wonders whether they play roles in tissue repair in addition to producing the keratinocyte growth factor.

"Do they produce other cytokines and chemokines as well?" Havran asks.

In preliminary data, they have seen that gd T cells have the ability to recruit ab T cells and monocytes, the white blood cell precursor of the macrophage cells, which play a central role in inflammatory responses.

"We are now looking at the mechanisms of that recruitment," says Havran.

Cancer, Asthma, Psoriasis, and Ulcerative Colitis

Quite apart from the basic science, Havran and Jameson's findings should be of interest to doctors who treat diseases that arise from epithelial cell disorders. These findings may eventually lead to the discovery of chemical compounds that could be used to treat conditions like cancer, psoriasis, ulcerative colitis, and asthma. Furthermore, the models Havran and Jameson used in the current study will provide useful test beds for assaying potential compounds against these conditions.

Asthma is a chronic disease where inflammation in the lungs narrows the small airways. The Centers for Disease Control and Prevention (CDC) estimates that in the year 1998, the most recent for which data were available, some 6.8 million adults in the United States and 3.8 million American children experienced an asthma attack. The more severe among them resulted in about 2 million emergency room visits, half a million hospitilizations, and 5,438 deaths that year.

Ulcerative colitis is a painful chronic disease characterized by inflammation and ulceration of the colon and large intestine. Ulcerative colitis and a similar condition known as Crohn's Disease afflict about one million Americans.

Psoriasis is a chronic disease of the skin that afflicts an estimated two percent of the population. Though generally quite mild, it can cause a great deal of discomfort in those who suffer from it.

Havran and Jameson's findings may be relevant to certain types of cancer because gd T cells are cytotoxic and have the ability to kill tumor cells.

Knowing the role of these cells in the skin and the mechanism whereby they interact with other skin cells may yield potential targets for intervention in all of these conditions. For instance, there is a correlation between asthma and the number of gd T cells in the lungs. During an attack, the number of gd T cells is elevated, which may be the body's attempt to deal with the problem.

Treatments that are based on a thorough understanding of the underlying mechanisms of gd T cells may prove to be better than currently existing therapy. Current treatments for asthma, ulcerative colitis, and psoriasis include anti-inflammatories like aspirin and corticosteroids, which shut down the response of the ab T cells. Havran suspects that this sort of treatment is sub-optimal because it also kills the gd T cells.

"These gd T cells are also important for tissue repair," she says. "We think the steroids delay tissue repair by killing off the gd T cells.

"We hope that this [work] will lead to new therapeutic agents that spare the gd T cells," says Havran.


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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.














Dendritic epidermal T cells (red) interact with neighboring keratinocytes (blue). The dendritic morphology of the gdT cells allows for intimate contact between these resident skin cells. Epidermal tissue was stained with DAPI and a gd T cell receptor-specific antibody.