Nav: Home

How IL-6 allows the immune response to develop for a key cell, the T follicular helper

September 13, 2019

BIRMINGHAM, Ala. - The body's immune response fights against infectious disease, and it safeguards against future infections through vaccination. However, if the immune response dysfunctions and attacks the body itself, it can cause autoimmune disease. Thus, a healthy immune response balances an instant readiness to combat infecting viruses or bacteria, while maintaining benign surveillance of the body's own tissues.

A key player in the immune response is T follicular helper cells. These Tfh cells are essential in vaccination responses, but they can be harmful actors in an autoimmune disease like lupus.

Now, a preclinical study published in Science Immunology shows how the interplay of two interleukin signaling proteins, IL-6 and IL-2, affects the development of Tfh cells. This interplay may either maintain or disrupt the balancing act of the immune system. Thus, the research may help guide future disease treatment.

"We believe these findings have important therapeutic implications," said André Ballesteros-Tato, Ph.D., associate professor in the University of Alabama at Birmingham Department of Medicine's Division of Clinical Immunology and Rheumatology and leader of the research.

"For example, it is well-known that abnormal expansion of Tfh cells correlates with disease severity in systemic lupus erythematosus patients. Unfortunately, there are currently no therapies to selectively deplete Tfh cells in vivo. Based on our data, it is tempting to speculate that blockade of IL-6 with IL-6-neutralizing antibodies -- in combination with recombinant IL-2 administration -- will synergize to efficiently prevent Tfh cell responses in autoimmune patients, thereby avoiding the production of self-reactive antibodies."

Both IL-6-neutralizing antibodies and recombinant IL-2 are Food and Drug Administration-approved drugs.

"The findings in this study are quite exciting," said S. Louis Bridges, Jr., M.D., Ph.D., director of the UAB Division of Clinical Immunology and Rheumatology. "Both IL-6 and IL-2 are key molecules in immune responses and autoimmune diseases. This research helps to elucidate the complex interactions of these cytokines and how they influence Tfh cells. The novel findings in this paper may ultimately lead to better ways to treat diseases such as lupus."

Development of Tfh cells takes place this way -- Tfh cells react with antigens presented outside of B cell follicles in the lymph nodes or spleen. The activated Tfh cells then move into the follicles, where the Tfh cells interact with B cells to produce a germinal center -- a factory that multiplies and transforms B cells into high-specificity, antibody-producing cells.

The study began from an apparent paradox for the UAB researchers and colleagues in Virginia and Maryland. As Tfh cells become germinal center-Tfh cells, they need sustained T-cell receptor stimulation to maintain the germinal center-Tfh state. Yet that same stimulation is known to induce expression of the interleukin-2 receptor and production of the interleukin IL-2, which together should create a feedback loop of IL-2 signaling that is known to inhibit Tfh cells. Therefore, Ballesteros-Tato and colleagues sought to understand how Tfh cells evade this potent inhibition.

They and others previously have shown that treatment with recombinant IL-2 prevents Tfh cell responses in mice. In the Science Immunology paper, using a model of influenza infection in mice, they found that IL-6 protects Tfh cells from the deleterious effect of IL-2 by interrupting the feedback loop. This effect allows Tfh cells to receive T-cell receptor stimulation without responding to IL-2. Part of the proof of this interplay was showing that blockade of IL-6 signaling rendered Tfh cells more susceptible to IL-2-mediated depletion, at lower levels of IL-2.

The researchers found that IL-6 protection was not needed in the first week of the immune response, apparently because other immune cells that consume IL-2 are present, lowering IL-2 levels. The IL-6 protection became essential after the Tfh cells entered B cell follicles to start germinal center development. There, the IL-2 produced by Tfh cells, Ballesteros-Tato says, is not consumed, which likely lets IL-2 levels rise past a threshold that requires IL-6 protection.

The research revealed underlying mechanistic details. The researchers found that IL-6 inhibited upregulation of the IL-2 beta receptor subunit, also called CD122, by preventing association of the STAT5 transcription factor with the Il2rb gene for that receptor subunit. This allowed the germinal center-Tfh cells that received sustained T-cell receptor signaling and were producing IL-2 to circumvent the T-cell receptor/IL-2-inhibitory feedback loop because the receptor cannot function.

Altogether, these results have identified a regulatory mechanism that controls the generation of germinal center-Tfh cells. Instead of one interleukin or another controlling the response of Tfh cells in an on-off fashion, IL-6 signaling fine-tunes the threshold of IL-2 responsiveness; thus, the relative levels of the two interleukins determine the fate of the Tfh cells.

This model, Ballesteros-Tato says, clarifies previous conflicting studies regarding the role of IL-6 in controlling Tfh cell responses.
-end-
First author, along with corresponding author Ballesteros-Tato, of the Science Immunology report, "Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-Tfh cells," is Amber Papillion, postdoctoral fellow in UAB Department of Medicine, Division of Clinical Immunology and Rheumatology. "Papillion is a great example of an outstanding young scientist whose cutting-edge research will help us better understand autoimmune diseases," Bridges said.

Co-authors are Michael D. Powell and Kenneth J. Oestreich, Virginia Tech Carilion Research Institute, Roanoke, Virginia; Danielle A. Chisolm, Amy S. Weinmann and Beatriz León, UAB Department of Microbiology; Holly Bachus and Michael J. Fuller, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; and Alejandro Villarino and John J. O'Shea, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.

Support came from the University of Alabama at Birmingham; National Institutes of Health grants AI110480, AI116584, AI061061, AI127800 and AI134972; and Intramural Research Program funds from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Papillion was supported by NIH Training Program in Rheumatic and Musculoskeletal Diseases Research, T32 AR069516.

University of Alabama at Birmingham

Related Immune Response Articles:

Researchers decode the immune response to Ebola vaccine
The vaccine rVSV-EBOV is currently used in the fight against Ebola virus.
Immune response depends on mathematics of narrow escapes
The way immune cells pick friends from foes can be described by a classic maths puzzle known as the 'narrow escape problem'.
Signature of an ineffective immune response to cancer revealed
Our immune system is programmed to destroy cancer cells. Sometimes it has trouble slowing disease progression because it doesn't act quickly or strongly enough.
Putting the break on our immune system's response
Researchers have discovered how a tiny molecule known as miR-132 acts as a 'handbrake' on our immune system -- helping us fight infection.
Having stressed out ancestors improves immune response to stress
Having ancestors who were frequently exposed to stressors can improve one's own immune response to stressors, according to Penn State researchers.
Researchers discovered new immune response regulators
The research groups of Academy Professor Riitta Lahesmaa and Research Director Laura Elo from Turku Centre for Biotechnology have discovered new proteins that regulate T cells in the human immune system.
Blueprint for plant immune response found
Washington State University researchers have discovered the way plants respond to disease-causing organisms, and how they protect themselves, leading the way to potential breakthroughs in breeding resistance to diseases or pests.
Immune response mechanism described for fate determination of T cells
In a paper published in the journal Science, University of Alabama at Birmingham researchers and colleagues at four other United States institutions have detailed a mechanism that sets the stage for the fate decision that gives rise to two major subsets of effector cells: T follicular helper cells and non-T follicular helper cells, known as Tfh and non-Tfh cells.
Retinoic acid may improve immune response against melanoma
University of Colorado Cancer Center clinical trial results describe a promising strategy to remove one of melanoma's most powerful defenses: By adding retinoic acid to standard-of-care treatment, researchers were able to turn off myeloid-derived suppressor cells (MDSCs) that turn off the immune system, leading to more immune system activity directed at melanoma.
Enzyme lays the foundations for allergic immune response
While in search of the causes of allergies and asthma, a chance discovery has yielded new clues: researchers led by Dr Marcus Peters have ascertained that the enzyme guanylate cyclase in cells lays the foundations for the type of immune response.
More Immune Response News and Immune Response Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.