Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Exhausted T cells

20.12.2016

LJI researchers map genome-wide changes that drive T cell maturation and exhaustion

In a bid to better understand the gene expression patterns that control T cell activity, researchers at the La Jolla Institute for Allergy and Immunology mapped genome-wide changes in chromatin accessibility as T cells respond to acute and chronic virus infections. Their findings, published in the Dec. 20, 2016 issue of Immunity, shed light on the molecular mechanisms that determine the fate of T lymphocytes and open new approaches to clinical intervention strategies to modulate T cell activity and improve immune function.


T cells (shown in gray) attacking cancer cells.

Credit: La Jolla Institute for Allergy and Immunology

"Identifying the different factors that determine different T cell states and therefore their function helps us understand if T cells will be able or not to fight viral infections or tumor growth, and if they will be able or not to provide long-term protection," says the study's first author James Scott-Browne, a postdoctoral fellow in the laboratory of Anjana Rao, a professor in the Division of Signaling and Gene Expression. "We may be able to revert the exhaustion phenotype of T cells and render them better able to fight tumors or chronic viral infections such as HIV, or generate better memory cells in response to vaccines."

When viruses invade or cells turn malignant, the immune system mobilizes a small cohort of naïve or immature CD8 T cells, a crucial subdivision of the immune system charged with killing virus-infected and cancerous cells. Upon activation, they mature and proliferate exponentially into highly specific effector T cells that eliminate virus-infected or otherwise compromised cells. After their job is done, most effector T cells die leaving behind only a small contingent of memory T cell that confer long-term protection.

In the face of chronic viral infections such as hepatitis and HIV as well as certain types of cancers, however, activated CD8 T cells are unable to gain the upper hand and clear the threat. As a result, CD8 T cells start to express inhibitory cell surface receptors that transmit inhibitory signals into the cell establishing a negative feedback loop. The mechanism is designed to prevent excessive immune responses from taking hold but it leaves CD8 T cells unable to fight foreign invaders effectively and forces them into a state known as "T cell exhaustion."

In earlier work, Rao and her team had pinpointed a transcription factor known as NFAT as the molecular linchpin that orchestrates T cell activation and exhaustion. When the T cell receptor on the surface of CD8 T cells recognizes a foreign protein, it kicks off a signaling cascade that culminates in the activation of NFAT and its partner AP-1.

Together, the pair binds to regulatory regions in the genome and initiates a genetic program that activates T cells and readies them to fight cancer and viral infections. When acting on its own, NFAT shifts the equilibrium from an activated to an exhausted state by binding to a different subset of regulatory regions within the genome, impairing the immune system's response to tumors and infection.

The current study expands the previous experiments, which were largely based on lab-grown T cells, to T cells isolated from mice with acute or chronic viral infections. It centered on a powerful methodology known as ATAC-seq, which pinpoints "open" or accessible stretches of chromatin. Chromatin is the sum total of genomic DNA and all associated proteins, which not only packages and condenses DNA but also helps control gene expression by giving or denying access to transcription factors. Knowing which regulatory sites in the genome are open for business allows scientists to conclude which transcription factors play a role in certain biological processes.

"We showed that when naïve cells are transformed into effector cells, there are big changes in the regions of chromatin near the genes that determine an "activated fate", explains co-lead author Renata Pereira, formerly a postdoctoral researcher in the Rao laboratory, and now an assistant professor at the Universidade Federal do Rio de Janeiro in Brazil. "In contrast the chromatin structure of effector cells is quite similar to that in memory or exhausted cells, suggesting that the differences in the functions of these cell types depend mostly on the action of transcription factors that bind the already open chromatin regions. So transcription factors could be a more interesting target to modulate the function of T cells than proteins that modulate if the chromatin is more or less accessible."

The work was funded by the National Institutes of Health (R01 AI40127) (to A.R.). the Damon Runyon Cancer Research Foundation, and the Pew Latin American Fellows Program in the Biomedical Sciences.

###

Full citation: " Genome-wide changes in chromation accessibility in CD8 T cells during viral infection." James P. Scott-Browne, Isaac F. López-Moyado, Sara Trifari, Victor Wong, Lukas Chavez, Anjana Rao, and Renata M Pereira. Immunity, 2016.

DOI: 10.1016/j.immuni.2016.10.028

URL: http://www.cell.com/immunity/fulltext/S1074-7613(16)30439-3.

About La Jolla Institute for Allergy and Immunology

The La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.

Media Contact

Jessica Roi
jroi@lji.org
858-752-6645

 @liairesearch

http://www.liai.org 

Jessica Roi | EurekAlert!

More articles from Life Sciences:

nachricht New eDNA technology used to quickly assess coral reefs
18.04.2019 | University of Hawaii at Manoa

nachricht New automated biological-sample analysis systems to accelerate disease detection
18.04.2019 | Polytechnique Montréal

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

A stellar flare 10 times more powerful than anything seen on our sun has burst from an ultracool star almost the same size as Jupiter

  • Coolest and smallest star to produce a superflare found
  • Star is a tenth of the radius of our Sun
  • Researchers led by University of Warwick could only see...

Im Focus: Quantum simulation more stable than expected

A localization phenomenon boosts the accuracy of solving quantum many-body problems with quantum computers which are otherwise challenging for conventional computers. This brings such digital quantum simulation within reach on quantum devices available today.

Quantum computers promise to solve certain computational problems exponentially faster than any classical machine. “A particularly promising application is the...

Im Focus: Largest, fastest array of microscopic 'traffic cops' for optical communications

The technology could revolutionize how information travels through data centers and artificial intelligence networks

Engineers at the University of California, Berkeley have built a new photonic switch that can control the direction of light passing through optical fibers...

Im Focus: A long-distance relationship in femtoseconds

Physicists observe how electron-hole pairs drift apart at ultrafast speed, but still remain strongly bound.

Modern electronics relies on ultrafast charge motion on ever shorter length scales. Physicists from Regensburg and Gothenburg have now succeeded in resolving a...

Im Focus: Researchers 3D print metamaterials with novel optical properties

Engineers create novel optical devices, including a moth eye-inspired omnidirectional microwave antenna

A team of engineers at Tufts University has developed a series of 3D printed metamaterials with unique microwave or optical properties that go beyond what is...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

Fraunhofer FHR at the IEEE Radar Conference 2019 in Boston, USA

09.04.2019 | Event News

 
Latest News

New automated biological-sample analysis systems to accelerate disease detection

18.04.2019 | Life Sciences

Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

18.04.2019 | Physics and Astronomy

New eDNA technology used to quickly assess coral reefs

18.04.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>