Lymph node structural cells rein in human immune responses

September 5, 2018, Public Library of Science
Section of a human tonsil depicting T cells (green) interacting with the FRC structural cells (red). COX2 (blue) is part of one of the mechanisms described that the structural cells use to control T cells (green). Credit: Sara Cruz Migoni

Until now, the study of the immune system has focused almost exclusively on white blood cells, and T cells in particular, as the body's major infection fighters. However, new research published September 4th in the open access journal PLOS Biology by Dr. Anne Fletcher and Dr. Konstantin Knoblich and colleagues, from the Monash Biomedicine Discovery Institute (BDI), has veered away from traditional immunology by turning the spotlight on the structural cells that build and support the immune-rich environment of lymph nodes. Their research shows that the so-called Fibroblastic Reticular Cells (FRCs) that form the inner structure of human tonsils and lymph nodes exert control over T cells and their response to infection.

These larger structural cells provide both structural support and guidance to while they spend time in lymph nodes, and the researchers' new work identifies four key mechanisms by which the FRCs act to dampen down T .

The four mechanisms that FRCs use include pathways involving prostaglandin E2, the adenosine 2a receptor, indoleamine-2,3-dioxygenase, and transforming growth factor beta. The scientists were able to inhibit all four FRC mechanisms using existing drugs, and found that T cell responses were heightened in the process. Once T cells are no longer suppressed by FRCs they are readily able to expand and proliferate.

Using an entirely novel approach, the researchers, in collaboration with University of Birmingham, examined the activation of T cells within live slices of human tonsil, and found that (in the presence or absence of key molecules), the T cells demonstrated a heightened when FRCs were inhibited.

"It's like finding out that the walls of a home control the people living in it. It is quite a surprise to most immunologists, who—understandably—have always focused on the people, or in this case, T cells," Dr. Fletcher said, who also has an honorary role at the University of Birmingham.

"This is of great significance as we are finally able to awaken the action of T cells when they are immunosuppressed in a natural setting. This is a new, clinically-relevant technique, offering a middle ground between in vitro work and human clinical trials," Dr. Knoblich said. "It allows researchers to test the clinical relevance of their immune-targeting therapy in live human tonsil tissue, which is readily available and often discarded in surgery."

These findings will help researchers understand why T cells respond differently when activated in the test-tube, compared to their response in a live human tissue, which contains a complex microenvironment and FRCs.

The work may help efforts to improve immune responses in situations where T don't work as well as they should, such as in the elderly, who are very susceptible to infections like influenza, and whose immune system or vaccination response may benefit from being boosted.

"While these mechanisms of suppression are a new part of our understanding of the human biology they can also form a new platform to study metastatic cancer," Dr. Fletcher said. "Metastasis of cancers often starts in the , and having a new variety of mechanisms to target can spark a number of new research platforms on the basis of these FRCs."

Explore further: How intestinal worms hinder tuberculosis vaccination

More information: Konstantin Knoblich et al, The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation, PLOS Biology (2018). DOI: 10.1371/journal.pbio.2005046

Related Stories

How intestinal worms hinder tuberculosis vaccination

May 17, 2018
New research in mice suggests that chronic infection with intestinal worms indirectly reduces the number of cells in lymph nodes near the skin, inhibiting the immune system's response to the Bacille Calmette-Guerin (BCG) ...

Understanding immune system interplay to improve organ transplant success

May 31, 2018
A rare opportunity to analyse both blood and tissue samples from human transplant recipients has allowed immunology researchers at the Babraham Institute to pinpoint how an immunosuppressive drug works to prevent the production ...

Study reveals that adrenergic nerves control immune cells' daily schedule

October 31, 2016
Researchers in Japan have discovered that the adrenergic nervous system controls when white blood cells circulate through the body, boosting the immune response by retaining T and B cells in lymph nodes at the time of day ...

Worm infection reveals cross-talk in the lymph nodes

August 28, 2017
By studying a worm infection, EPFL scientists have discovered how lymphatic vessels grow within lymph nodes, with major implications for cancer and inflammation.

Revving up innate control of viral infection requires a three-cell ignition

July 5, 2018
One of the most important cell types for controlling certain viral infections are natural killer (NK) cells. As part of the innate and rapid immune response, NK-cell recruitment and activation was thought to be a straightforward ...

Treatment with lymph node cells controls dangerous sepsis in animal models

August 13, 2014
An immune-regulating cell present in lymph nodes may be able to halt severe cases of sepsis, an out-of-control inflammatory response that can lead to organ failure and death. In the August 13 issue of Science Translational ...

Recommended for you

Paracetamol use in infancy is linked to increased risk of asthma in some teenagers

September 17, 2018
Children who take paracetamol during their first two years of life may be at a higher risk of developing asthma by the age of 18, especially if they have a particular genetic makeup, according to new research presented at ...

Cord blood clue to respiratory diseases

September 15, 2018
New research has found children born in the last three months of the year in Melbourne may have a greater risk of developing respiratory diseases such as asthma.

FRESH program combines basic science with social benefits for women at risk of HIV

September 14, 2018
A program established by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard is addressing the persistently elevated risk of HIV infection among young women in South Africa from ...

Dietary fiber reduces brain inflammation during aging

September 14, 2018
As mammals age, immune cells in the brain known as microglia become chronically inflamed. In this state, they produce chemicals known to impair cognitive and motor function. That's one explanation for why memory fades and ...

Research reveals link between immunity, diabetes

September 14, 2018
When it comes to diet-induced obesity, your immune system is not always your friend.

Immune response mechanism described for fate determination of T cells

September 13, 2018
After a pathogen infects the body, the immune system responds with a remarkable—and remarkably complicated—cascade of events.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.