Nav: Home

Novel genomic tools provide new insight into human immune system

January 19, 2018

LA JOLLA, CA--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 cell types we are changing our understanding of the biology of human immune cells."

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 chronic viral infections 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 cells. Her analysis uncovered remarkable heterogeneity between individual cells 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.
-end-
This work was supported by NIH grants U19AI118626 and U19AI118610; R01HL114093 and R24AI108564, S10OD016262 and S10RR027366, the William K. Bowes Jr. Foundation, and NIH contract nos. HHSN272200900042C and HHSN27220140045C.

Full citation:

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

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.

La Jolla Institute for Allergy and Immunology

Related Hiv Articles:

Defective HIV proviruses reduce effective immune system response, interfere with HIV cure
A new study finds defective HIV proviruses, long thought to be harmless, produce viral proteins and distract the immune system from killing intact proviruses needed to reduce the HIV reservoir and cure HIV.
1 in 7 people living with HIV in the EU/EEA are not aware of their HIV status
Almost 30,000 newly diagnosed HIV infections were reported by the 31 European Union and European Economic Area (EU/EEA) countries in 2015, according to data published today by ECDC and the WHO Regional Office for Europe.
Smoking may shorten the lifespan of people living with HIV more than HIV itself
A new study led by researchers at Massachusetts General Hospital finds that cigarette smoking substantially reduces the lifespan of people living with HIV in the US, potentially even more than HIV itself.
For smokers with HIV, smoking may now be more harmful than HIV itself
HIV-positive individuals who smoke cigarettes may be more likely to die from smoking-related disease than the infection itself, according to a new study published in the Journal of Infectious Diseases.
Patients diagnosed late with HIV infection are more likely to transmit HIV to others
An estimated 1.2 million people live with HIV in the United States, with nearly 13 percent being unaware of their infection.
The Lancet HIV: New HIV infections stagnating at 2.5 million a year worldwide
A major new analysis from the Global Burden of Disease 2015 study, published today in The Lancet HIV journal, reveals that although deaths from HIV/AIDS have been steadily declining from a peak in 2005, 2.5 million people worldwide became newly infected with HIV in 2015, a number that hasn't changed substantially in the past 10 years.
NIH scientists discover that defective HIV DNA can encode HIV-related proteins
Investigators from the National Institutes of Health have discovered that cells from HIV-infected people whose virus is suppressed with treatment harbor defective HIV DNA that can nevertheless be transcribed into a template for producing HIV-related proteins.
Study examines risk of HIV transmission from condomless sex with virologically suppressed HIV infection
Among nearly 900 serodifferent (one partner is HIV-positive, one is HIV-negative) heterosexual and men who have sex with men couples in which the HIV-positive partner was using suppressive antiretroviral therapy and who reported condomless sex, during a median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission, according to a study appearing in the July 12 issue of JAMA, an HIV/AIDS theme issue.
HIV vaccine design should adapt as HIV virus mutates
Researchers from UAB, Emory and Microsoft demonstrate that HIV has evolved to be pre-adapted to the immune response, worsening clinical outcomes in newly infected patients.
Charlie Sheen's HIV disclosure may reinvigorate awareness, prevention of HIV
Actor Charlie Sheen's public disclosure in November 2015 that he has the human immunodeficiency virus (HIV) corresponded with the greatest number of HIV-related Google searches ever recorded in the United States, according to an article published online by JAMA Internal Medicine.

Related Hiv Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Bias And Perception
How does bias distort our thinking, our listening, our beliefs... and even our search results? How can we fight it? This hour, TED speakers explore ideas about the unconscious biases that shape us. Guests include writer and broadcaster Yassmin Abdel-Magied, climatologist J. Marshall Shepherd, journalist Andreas Ekström, and experimental psychologist Tony Salvador.
Now Playing: Science for the People

#513 Dinosaur Tails
This week: dinosaurs! We're discussing dinosaur tails, bipedalism, paleontology public outreach, dinosaur MOOCs, and other neat dinosaur related things with Dr. Scott Persons from the University of Alberta, who is also the author of the book "Dinosaurs of the Alberta Badlands".