Novel genomic tools provide new insight into human immune system

January 19, 2018, La Jolla Institute for Allergy and Immunology

When the body is under attack from pathogens, the immune system marshals a diverse collection of immune cells to work together in a tightly orchestrated process and defend the host against the intruders. For many decades, immunologists sorted these cells into ever growing numbers of different types and subtypes mainly based on their morphology and phenotype to understand their function. But novel genomic tools are beginning to reveal new, rare cell types as well as unexpected variability and plasticity within groups upending the traditional view of immune cells assigned to the same category as unvarying entities that behave in a constant manner.

In their latest study, researchers at La Jolla Institute for Allergy and Immunology (LJI) used single-cell transcriptome analysis to identify a hitherto unknown precursor for a poorly understood subgroup of killer T cells that is primarily found in humans with chronic viral infections. Their detailed analysis of the entirety of transcribed genes in more than 9,000 individual cells also revealed an unprecedented level of heterogeneity.

The findings, published in the January 19, 2018, online edition of Science Immunology, provide new insights into how so-called CD4 cytotoxic T cells arise in humans and thus could facilitate improved vaccine design to protect against chronic viral infections such as cytomegalovirus, HIV, and hepatitis C.

"Continually evolving genomic tools and single cell analysis technologies are revolutionizing our understanding of the human immune system in health and disease," says Pandurangan Vijayanand, M.D., Ph.D., Associate Professor and William K. Bowes Jr. Distinguished Professor at LJI who led the study. "But this is just the beginning of the genomic journey. By applying these tools in relevant diseases and we are changing our understanding of the biology of human ."

Based on cell surface markers known as CD4 and CD8, T cells generally fall into two broad categories: CD4-positive helper T cells, which¬ help activate other immune cells and CD8-positive cytotoxic T cells, which kill cells that are cancerous or infected with viruses. Under certain circumstances, however, a portion of helper T cells turns into cytotoxic T cells (CD4-CTLs). CD4 CTLs were originally reported in humans with such as human cytomegalovirus (CMV), HIV, dengue virus and hepatitis C virus but have also been linked to protective antitumor immune responses, especially in virally induced tumors.

"The observed increase in the ratio of cytotoxic CD4 T cells to CD4 helper T cells indicates that they are an important component of the protective immune response to viral infections and that their induction should be an important marker for successful vaccinations against certain viral diseases," says postdoctoral researcher and first author Veena Patil, Ph.D. "But we really didn't know enough about their molecular profile and the mechanisms that drive their differentiation and maintenance."

To learn more, Patil analyzed thousands of individual CD4-CTLs isolated from peripheral blood from donors using single cell RNA sequencing, which can define different cell types and subtypes by revealing differences in the transcripts produced by individual . Her analysis uncovered remarkable heterogeneity between but also within individuals. "It is probably the result of the diverse nature of infections and timing of viral exposures coupled with genetic diversity among our study subjects," she says.

Vijayanand and his team were also able to identify a subset of CD4-CTLs precursors that potentially give rise to fully fledged CD4 CTLs in human. "Understanding the origins and biology of potentially long-lived CD4-CTL precursors may pave the way for developing strategies to boost durable CD4-CTL immune responses after vaccination against viral infections and cancer," the authors write in their paper.

Explore further: Cellular mechanism for severe viral hepatitis identified

More information: Veena S. Patil, Ariel Madrigal, Benjamin J. Schmiedel, James Clarke, Patrick O'Rourke, Aruna D. de Silva, Eva Harris, Bjoern Peters, Gregory Seumois, Daniela Weiskopf, Alessandro Sette, Pandurangan Vijayanand. Precursors of human CD4+ cytotoxic T lymphocytes identified by single-cell transcriptome analysis. Science Immunology, 2018. DOI: 10.1126/sciimmunol.aan8664

Related Stories

Cellular mechanism for severe viral hepatitis identified

January 18, 2018
KAIST medical scientists identified a cellular mechanism causing inflammatory changes in regulatory T cells that can lead to severe viral hepatitis. Research on this mechanism will help further understand the nature of various ...

Researchers makes 'natural born killer' cell discovery

August 31, 2017
An unexpected role for a white blood cell called the Natural Killer (NK) cell - a critical cell for ridding the body of infection and cancer, has been discovered by researchers at New Zealand's University of Otago.

Tumor immune fitness determines survival of lung cancer patients

June 19, 2017
In recent years, immunotherapy, a new form of cancer therapy that rouses the immune system to attack tumor cells, has captivated the public's imagination. When it works, the results are breathtaking. But more often than not ...

Can myeloid derived suppressor cells subdue viral infections?

January 26, 2017
Myeloid derived suppressor cells (MDSCs), produced in the bone marrow as part of the human immune response to a tumor, may have a potent immunoregulatory role following viral infection. The similarities and differences between ...

Cell marker enables prognosis about the course of infections

October 1, 2015
When a pathogen invades the body, specific cells in the human immune system are ready to take immediate action in order to destroy it. The molecular characteristics of these killer cells were unknown until recently. Now, ...

Reassigning cells to fight infection

April 26, 2013
Just as a uniform helps distinguish a soldier from a police officer, scientists use proteins that immune cells wear on their surfaces to determine their job in the body. T cells, for example, that display the CD8 protein ...

Recommended for you

Researchers identify source of molecule linked to nasal polyps, asthma attacks

May 23, 2018
A new discovery about how the immune system responds to common sinus infections and asthma could explain why patients develop these issues in the first place and ultimately may lead to improved targeted therapies. Researchers ...

Study demonstrates new treatment for severe asthma

May 22, 2018
Researchers from McMaster University and the Firestone Institute for Respiratory Health at St. Joseph's Healthcare Hamilton, together with colleagues at other partnering institutions, have developed a new method to treat ...

Eczema drug effective against severe asthma

May 21, 2018
Two new studies of patients with difficult-to-control asthma show that the eczema drug dupilumab alleviates asthma symptoms and improves patients' ability to breathe better than standard therapies. Dupilumab, an injectable ...

Neuron guidance factor found to play a key role in immune cell function

May 21, 2018
Macrophages are white blood cells involved in a variety of biological functions, from destroying infectious pathogens to repairing damaged tissue. To carry out their different roles, macrophages must first be activated and ...

Immune cells hold promise in slowing down ALS

May 21, 2018
Recent research from Houston Methodist Hospital showed that a new immunotherapy was safe for patients with ALS and also revealed surprising results that could bring hope to patients who have this relentlessly progressive ...

First clues to the causes of multiple sclerosis

May 16, 2018
Multiple sclerosis, which affects one in 1,000 people, is frequently characterised by relapses associated with variable functional impairments including among others vision problems, impairment of locomotor functions or difficulties ...

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.