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 Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg

nachricht Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>