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

December 19, 2016, La Jolla Institute for Allergy and Immunology
T cells (shown in gray) attacking cancer cells. Credit: La Jolla Institute for Allergy and Immunology

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.

"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 . 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 . 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 . 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 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 , 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 could be a more interesting target to modulate the function of T 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.

Explore further: The company you keep: Scientists reveal dual role for key T cell factor

Related Stories

The company you keep: Scientists reveal dual role for key T cell factor

February 12, 2015
When fighting chronic viral infections or cancers, a key division of the immune system, known as CD8 T cells, sometimes loses its ability to effectively fight foreign invaders. Overcoming so-called T cell exhaustion is crucial ...

Stability of exhausted T cells limits durability of cancer checkpoint drugs

October 27, 2016
Checkpoint inhibitor drugs that boost the immune system to fight cancer owe part of their existence to infectious diseases. Microbes that cause diseases like HIV, malaria, and hepatitis C exploit and often activate the same ...

Researchers reveal how two types of immune cells can arise from one

April 11, 2016
The fates of immune cells can be decided at the initial division of a cell. Researchers at St. Jude Children's Research Hospital have discovered that the production of daughter cells with different roles in the immune system ...

By taking a rest, exhausted T cells live to fight another day

January 26, 2015
Killer T cells are one of the body's main lines of defense against pathogens. Their job is to kill infected cells so that the viruses inside cannot replicate and spread. But often the force of their attack wanes during a ...

T cell revival through PD-1: Clues for cancer immunotherapy

August 2, 2016
Cancer immunotherapy drugs that block the inhibitory PD-1 pathway have shown success in clinical trials and are now FDA-approved for melanoma, lung cancer and bladder cancer. Yet many patients' tumors do not respond to these ...

Recommended for you

A bad influence—the interplay between tumor cells and immune cells

October 16, 2018
Research at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) yielded new insights into the environment surrounding different types of lung tumors, and described how these complex cell ecosystems may in turn ...

New immunotherapy targeting blood-clotting protein

October 15, 2018
Normally, the blood protein fibrin does not enter the brain. But in several neurological disorders, the blood-brain barrier—which keeps large molecules in the blood from entering the brain—becomes abnormally permeable, ...

Function of neutrophils during tumor progression unraveled

October 15, 2018
Researchers at The Wistar Institute have characterized the function of neutrophils, a type of white blood cells, during early stages of tumor progression, showing that they migrate from the bone marrow to distant sites and ...

Immune health maintained by meticulously ordered DNA

October 15, 2018
Walter and Eliza Hall Institute researchers have revealed how immune health is maintained by the exquisite organisation skills of a protein called Pax5.

Enzyme that triggers autoimmune responses from T-cells in patients with MS found

October 11, 2018
A team of researchers from Switzerland, the U.S. and Spain has isolated an enzyme that triggers an autoimmune response from T-cells in patients with MS. In their paper published in the journal Science Translational Medicine, ...

Scientists reveal new cystic fibrosis treatments work best in inflamed airways

October 11, 2018
A new UNC School of Medicine study shows that two cystic fibrosis (CF) drugs aimed at correcting the defected CFTR protein seem to be more effective when a patient's airway is inflamed. This is the first study to evaluate ...

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.