Unconventional T-Cell Subtype Is Competent Virus Fighter

A collaborative group of scientists led by investigators at the University of Birmingham have just identified a novel role for an enigmatic and unconventional subset of immune cells known as gamma delta T cells (Vδ2 T cells). The researchers examined how this subtype of T cell responded to a virus infection called cytomegalovirus. They found that when these T cells detected signs of the virus infection, they both increased in numbers and became “licensed to kill.” Findings from the new study were published today in Nature Communications (“The Human Vδ2⁺ T-Cell Compartment Comprises Distinct Innate-Like Vγ9⁺ and Adaptive Vγ9^– Subsets”).

This immune cell subset has a distinctive T-cell receptor (TCR) on its surface. While most T cells are αβ T cells with the TCR composed of two glycoprotein chains, called α and β TCR chains, γδ T cells have a TCR that is made up of one γ chain and one δ chain. Although γδ T cells are much less common than αβ T cells, they are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes.

αβ and γδ T cells are commonly thought to arise from a common precursor within the thymus gland yet perform distinct roles in pathogen resistance. Though conventional αβ T cells depart the thymus in a naïve state and acquire effector function in the periphery, the effector fate of many γδ T cells is defined in the thymus, and they exhibit limited plasticity after that.

The new findings establish that this subtype is not only present at birth, but persists in adults at low levels and can increase in numbers massively during virus infections.

“These cells can clearly adapt to some key challenges that life throws at them,” explained lead study investigator Martin Davey, Ph.D., research fellow at the University of Birmingham's Institute of Immunology and Immunotherapy. “Upon viral infection, they change from harmless precursors into what appear to be ruthless killers. They can then access tissues, where we believe they detect and destroy virally infected target cells.”

In the current study, the research team identified a subset of unconventional Vδ2 lymphocytes, which have historically been poorly understood.

“Vδ2⁺ T cells form the predominant human Vδ2T-cell population in peripheral blood and mediate T-cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity,” the authors wrote. “Here we show that the Vδ2⁺ compartment comprises both innate-like and adaptive subsets. Vγ9⁺ Vδ2⁺ T cells display semi-invariant TCR repertoires, featuring public Vγ9 TCR sequences equivalent in cord and adult blood. By contrast, we also identify a separate, Vγ9⁻ Vδ2⁺ T-cell subset that typically has a CD27^hiCCR7⁺CD28⁺IL-7Rα⁺ naive-like phenotype and a diverse TCR repertoire, however in response to viral infection, undergoes clonal expansion and differentiation to a CD27^loCD45RA⁺CX₃CR1⁺granzymeA/B⁺ effector phenotype.” 

The current results build on previous work from the same research group, which also suggests that many γδ T cells that control our immune system can adapt in the face of infectious challenges. Now, the researchers are trying to understand the scenarios better when these unconventional killer T cells are most important and how to harness them to advance treatments to fight viral infections.

“We think these cells contribute to defense against viral infection in the liver, a site that is exposed to many potentially dangerous infectious diseases,” Dr. Davey noted. “They may also be particularly important when other aspects of our immune system are not working at full strength, such as in newborn babies, but also in transplant patients who are taking immunosuppressive drugs to prevent organ rejection.

Dr. Davey concluded, stating that “in these scenarios, boosting the activity of these cells could prove beneficial to patients, and we are now starting to explore how to do that.”