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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