Cells
That ‘Taste’ Danger Set Off Immune Responses
Taste and smell receptors in
unexpected organs monitor the state of the body’s natural microbial health and
raise an alarm over invading parasites.
[[Everything is
much more complicated that we thought.]]
Cells with
taste receptors sometimes develop inside the lungs of animals infected with
influenza. By “tasting” the presence of certain pathogens, these cells may act
as sentinels for the immune system.
November 15, 2019
When the immunologist De’Broski
Herbert at the University of Pennsylvania looked deep inside
the lungs of mice infected with influenza, he thought he was seeing
things. He had found a strange-looking cell with a distinctive thatch of
projections like dreadlocks atop a pear-shaped body, and it was studded with
taste receptors. He recalled that it looked just like a tuft cell — a cell type
most often associated with the lining of the intestines.
But what would a cell covered
with taste receptors be doing in the lungs? And why did it only appear there in
response to a severe bout of influenza?
Herbert wasn’t alone in his
puzzlement over this mysterious and little-studied group of cells that keep
turning up in unexpected places, from the thymus (a small gland in the chest
where pathogen-fighting T cells mature) to the pancreas. Scientists are only
just beginning to understand them, but it is gradually becoming clear that tuft
cells are an important hub for the body’s defenses precisely because they can
communicate with the immune system and other sets of tissues, and because their
taste receptors allow them to identify threats that are still invisible to
other immune cells.
De’Broski
Herbert, an immunology researcher at the University of Pennsylvania, was the
first to notice the emergence of tuft cells, which are rich in “taste”
receptors, developing in the infected lungs of sick mice.
Researchers around the world are
tracing the ancient evolutionary roots that olfactory and taste receptors
(collectively called chemosensory receptors or nutrient receptors) share with
the immune system. A flurry of work in recent years shows that their paths
cross far more often than anyone anticipated, and that this
chemosensory-immunological network plays a role not just in infection, but in
cancer and at least a handful of other diseases.
This system, says Richard Locksley, an immunologist at the University of
California, San Francisco, helps direct a systematic response to potential
dangers throughout the body. Research focusing on the interactions of the tuft
cell could offer a glimpse of how organ systems work together. He describes the
prospects of what could come from the studies of these receptors and cells as
“exciting,” but cautions that “we’re still in the very early days” of figuring
it out.
Not Merely Taste and Smell Receptors
One of life’s fundamental
challenges is to find food that’s good to eat and avoid food that isn’t.
Outside of our modern world of prepackaged food on grocery store shelves, it’s
a perilous task. Taking advantage of a new type of food could mean the
difference between starvation and survival, or it could mean an early death
from accidental self-poisoning. Chemosensory receptors help us make this
distinction. They’re so essential that even single-celled bacteria such
as Escherichia coli carry a type of this receptor.
Despite the near universality of
these receptors and their centrality to survival, scientists didn’t discover
the big family of genes that encode for olfactory receptors until 1991, with
the ones for taste receptors following in 2000. (The olfactory receptor
discovery brought the researchers Richard
Axel and Linda Buck a Nobel Prize in 2004.) Olfactory receptors and taste
receptors for bitter, sweet and umami (savory) are all part of a large family
of proteins called G protein-coupled receptors (GPCRs) that are embedded in
cell membranes. Although the precise details vary from receptor to receptor,
when a GPCR binds to the proper molecule, it sets off a signaling cascade
within the cell. For taste and olfactory receptors in the mouth and nose, this
cascade causes neurons to fire and enables us to recognize everything from the
rich sweetness of a chocolate chip cookie to the nose-wrinkling stench of a
passing skunk.
The discoveries of these
receptors were momentous, groundbreaking advances, says Jennifer Pluznick,
a physiologist at Johns Hopkins University. But in her view, labeling them as
olfactory and taste receptors rather than as chemosensory receptors entrenched
the idea that they function specifically and exclusively in smell and taste. If
scientists found signs of these receptors in cells outside the nose and mouth, it
was easy to write them off as mistakes or anomalies. [[Why was it easy?
Because we already know everything so
this can’t change that.]] She herself was shocked to find an olfactory receptor
called Olfr78 in kidney cells, a finding that she reported in 2009.
“I think I even famously said
something to my postdoc adviser, like, ‘I don’t even know that I can trust this
data, you know?’” Pluznick recalled. “Olfactory receptors in the kidney? Come
on.”
This wasn’t the first time these
receptors had shown up in unexpected tissues. For example, in 2005, the
University of Liverpool biochemist Soraya Shirazi-Beechey showed in a paper published in Biochemical Society
Transactions that taste receptors could be found in the
small intestine as well as the mouth. Their presence was surprising, but it
made a certain sense that the intestine might use a taste receptor to monitor
the food it was digesting.
But then in 2010, the laboratory
of Stephen Liggett, who was then at the University of Maryland
School of Medicine, reported that smooth muscle in the airways of the lungs
expresses receptors for bitter taste. Moreover, they showed that these
receptors were involved in a dilation response of the airways that helped to
clear out obstructions.
They were these really
intriguing, weird cells that didn’t really have a clear function in terms of
the normal physiology.
Michael Howitt, Stanford
University
Receptors for sweetness also
turned up on the cells lining the airways. In 2012, a research group led by
Herbert’s colleague Noam Cohen at the University of Pennsylvania found
that the sugars coating the respiratory pathogen Pseudomonas aeruginosa activated
those receptors and caused the cells to beat their hairlike cilia more rapidly,
a process that can sweep away invading bacteria and prevent infections.
Meanwhile, Pluznick and her
colleagues had continued to study the role of the Olfr78 receptor in the
kidneys. They demonstrated in 2013 that it responded to molecules
secreted by intestinal microorganisms, and that signals from that response
helped to direct the kidney’s secretion of the hormone renin, which
regulates blood pressure. “Other labs finding similar things in other
tissues was both very encouraging and very exciting,” Pluznick said.
These studies and a torrent of
others from labs around the world drove home the message that these seemingly
misplaced olfactory and taste receptors serve important and often vital
functions.
And a theme common to many of those functions was that the chemosensory
receptors often seemed to be alerting tissues to the presence and condition of
microbes in the body. In hindsight, that application for the receptors made a
lot of sense. For example, as Herbert notes, being able to “taste” and “smell”
minute traces of pathogens gives the body more chances to respond to infections
before microbes overwhelm the host’s defenses.
A Job for Tuft Cells
In researchers’ assays for
chemosensory receptors in tissues throughout the body, a cell type that kept
popping up was a relatively rare, largely unstudied one called a tuft cell.
Tuft cells had been known to science since the mid-1950s, when microscopy
studies found them in the lining of practically every organ in the body,
including the gut, the lungs, the nasal passages, the pancreas and the
gallbladder. The passage of a half-century, however, hadn’t led to any
greater understanding of what tuft cells do. The further discovery of taste
receptors on many tuft cells only deepened the mystery: Given their locations
in the body, they certainly weren’t contributing to our sense of taste.
As a postdoc at Harvard
University in the lab of Wendy
Garrett in 2011, Michael
Howitt became fascinated with tuft cells, especially those found in
the intestines. “They were these really intriguing, weird cells that didn’t
really have a clear function in terms of the normal physiology,” said Howitt,
who is now an immunologist at Stanford University. He set out to learn the
enigmatic cells’ function, and he eventually got his answer — through an
unexpected discovery involving the mouse microbiome.
Howitt’s findings were
significant because they pointed to a possible role for tuft cells in the
body’s defenses — one that would fill a conspicuous hole in immunologists’
understanding.
Because some studies had hinted
at a link between taste receptors and immune function, Howitt wondered whether
the receptor-studded tuft cells in the intestines might respond to the
microbiome population of bacteria living in the gut. To find out, he turned to
a strain of mice that other Harvard researchers had bred to lack a wide variety
of bacterial pathogens.
But surprisingly, when he
inspected a small sample of intestinal tissue from the mice, Howitt found that
they had 18 times the number of tuft cells previously reported. When he looked
more closely, he found that the mice carried more protozoa in their guts than
expected — specifically, a common single-celled parasite called Tritrichomonas
muris.
Howitt realized that T.
muris wasn’t an accidental infection but rather a normal part of the
microbiome in mice — something that neither he nor Garrett had thought much
about. “We weren’t looking for protozoa,” Howitt said. “We were focused on
bacteria.”
To confirm the relationship
between the presence of the protozoa and the elevated numbers of tuft cells,
Howitt ordered another set of similarly pathogen-free mice from a different breeding
facility and fed them some of the protozoan-rich intestinal contents of the
Harvard mice. The number of tuft cells in the new mice soared as the parasites
colonized their intestines, too.
The numbers of tuft cells also
climbed when Howitt infected mice with parasitic worms. But the increase didn’t
happen in mice with defects in the biochemical pathways underpinning their
taste receptors, including those on the tuft cells.
Howitt’s findings were
significant because they pointed to a possible role for tuft cells in the
body’s defenses — one that would fill a conspicuous hole in immunologists’
understanding. Scientists understood quite a bit about how the immune system
detects bacteria and viruses in tissues. But they knew far less about how the
body recognizes invasive worms, parasitic protozoa and allergens, all of which
trigger so-called type 2 immune responses. Howitt and Garett’s work suggested
that tuft cells might act as sentinels, using their abundant chemosensory
receptors to sniff out the presence of these intruders. If something seems
wrong, the tuft cells could send signals to the immune system and other tissues
to help coordinate a response.
At the same time that Howitt was
working, Locksley and his postdoc Jakob von Moltke (who now runs his own lab at the
University of Washington) were homing in on that finding from another
direction by studying some of the chemical signals (cytokines) involved in
allergies. Locksley had discovered a group of cells called group 2 innate
lymphoid cells (ILC2s) that secrete these cytokines. ILC2s, he found, release
cytokines after receiving a signal from a chemical called IL-25. Locksley and
von Moltke used a fluorescent tag to mark intestinal cells that produced IL-25.
The only cells that gave off a red glow in their experiments were tuft cells.
Locksley had barely even heard of them.
“Even textbooks of
[gastrointestinal] medicine had no idea what these cells did,” he said.
Andrew
Vaughan, a lung researcher at the University of Pennsylvania, notes that
even if the sudden emergence of tuft cells in infected tissues is part of the
body’s defenses, it could still cause its own pathologies.
Courtesy of University of
Pennsylvania School of Veterinary Medicine
The Howitt-Garrett and
Locksley-von Moltke papers were prominently featured in Science and Nature,
respectively. Together with a third
paper in Nature by Philippe
Jay of the Institute for Functional Genomics at the National Center
for Scientific Research in France and his colleagues, these studies provided
the first explanation for what tuft cells do: They recognize parasites by means
of a small molecule called succinate, an end product of parasite metabolism.
Once succinate binds to a tuft cell, it triggers the release of IL-25, which
alerts the immune system to the problem. As part of the defensive cascade, the
IL-25 also helps to initiate the production of mucus by nearby goblet cells and
triggers muscle contractions to remove the parasites from the gut.
For the first time, biologists
had found at least one explanation for what tuft cells do. Before this, “people
just kind of ignored them or didn’t even realize that they were there,”
said Megan
Baldridge, a molecular microbiologist at Washington University in St.
Louis.
As groundbreaking as this trio of
studies was, the work focused on intestinal cells. No one knew at first whether
the tuft cells appearing elsewhere throughout the body play the same
anti-parasitic role. Answers soon began to roll in, and it became clear that
tuft cells respond to more than succinate and do more than help repel the
body’s invaders. In the thymus (a small globular outpost of the immune system
nestled behind the breastbone), tuft
cells help teach the immune system’s maturing T cells the difference
between self proteins and non-self proteins. Kathleen DelGiorno,
now a staff scientist at the Salk Institute for Biological Studies, helped to
show that tuft cells can help protect against pancreatic cancer
by detecting cellular injury. And in Cohen’s studies of chronic nasal and sinus
infection, he discovered that recognition of bacterial pathogens such as Pseudomonas
aeruginosa by receptors for bitterness on tuft cells causes
neighboring cells to pump out microbe-killing chemicals.
As a lung biologist and a
colleague of Herbert’s at the University of Pennsylvania, Andrew Vaughan followed these tuft-cell discoveries
with interest. In many cases, tuft cells appeared to be intimately involved
with the part of the immune response known as inflammation. Vaughan was
studying how tissue deep in the lungs repairs itself after inflammation caused
by the flu virus. After reading about some of the new findings, Vaughan began
to wonder whether tuft cells might be involved in the lungs’ recovery from
influenza. He and Herbert infected mice with the influenza virus and searched
the lungs of those with severe symptoms for signs of tuft cells.
“Sure enough, they were all over
the place,” Vaughan said. But the tuft cells only appeared after influenza
infection, which made Vaughan believe that he and Herbert were “basically
seeing a cell type where [it’s] not supposed to be.” Although he’s unsure exactly
why this proliferation of tuft cells happens after the flu, Vaughan speculates
that it might be an aspect of the body’s attempt to repair damage from the
virus as part of the broader type 2 immune response.
The researchers don’t yet know
what the tuft cells are doing in the lungs or what they are sensing, but
Herbert believes that their ability to continually “taste” the environment for
different compounds provides a key opportunity for the body to respond to even
minute threats.
The tuft cell, Herbert said, is
constantly sensing the metabolic products present in microenvironments within
the body. “Once some of those metabolic products go out of whack … bam! Tuft
cells can recognize it and make a response if something is wrong.”
Newly discovered connections
between tuft cells and the immune and nervous systems provide further evidence
that chemosensory receptors are multipurpose tools like Swiss Army knives, with
evolved functions beyond taste and smell. It isn’t clear which function evolved
first, though, or whether they all evolved in tandem, Howitt says. Just because
scientists became aware of “taste” receptors on the tongue first, “that doesn’t
mean that’s the order in which it evolved
In fact, a preliminary study in
rats hints that the receptors’ immune functions may have evolved first. Two
groups of immune cells known as monocytes and macrophages use formyl peptide
receptors on their membranes to detect chemical cues from pathogens, and
a group
of Swiss scientists showed that rats use these same receptors to
detect pheromone odors. Those facts suggest that at some point in history, the
ancestors of rats made scent receptors out of the immunological molecules. The
evolutionary history of other groups of olfactory and taste receptors has yet
to be deciphered.
Whatever their history,
scientists now say that a major role of these receptors is to monitor the
molecules in our body, tasting and smelling them for any sign that they might
be from a pathogen. Then, with help from tuft cells and other parts of the
immune system, the body can fight off the invaders before they’ve gotten a foothold.
But Vaughan cautioned that the sudden emergence of tuft cells in tissues like
the lungs, where they are not always present, might also cause its own
pathologies.
“You may not always want to have
the ability to [defensively] overreact,” he said. That could be part of what
goes wrong in conditions like allergies and asthma: There could be dangers “if
you have too many of these cells and they’re too poised to respond to the
external environment.”
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