Virtual memory T cells provide nonspecific immunity for infants early in life

Findings from St. Jude Children’s Research Hospital demonstrate that virtual memory T cells, a specialized group of immune cells, provide nonspecific immunity for infants early in life. The work stems from a study dating to 2019, when St. Jude and collaborating institutions reported successful and safe gene therapy for multiple infants with X-linked Severe Combined Immunodeficiency (X-SCID), also called “bubble boy disease.” Children with X-SCID cannot form an immune system; however, the gene therapy fixed a critical mutation and enabled the patients to develop immunity. This gave St. Jude researchers the unique opportunity to study how the immune system forms. In doing so, they confirmed the existence of a group of cells that provides early nonspecific protection to human infants to give their long-term immune memory time to mature. The findings were published today in Immunity.

The gene therapy that corrected the mutation causing X-SCID was pioneered at St. Jude by the late Brian Sorrentino, MD, and the work continued under Stephen Gottschalk, MD, St. Jude Department of Bone Marrow Transplantation & Cellular Therapy. After receiving the therapy, the children’s immune systems started to form for the first time in their lives. As it is currently not possible to safely test the developing human immune system in utero, the researchers had the rare chance to watch early immunity emerge. They used patient blood samples to evaluate the immune cells that make up the early immune system and study what those cells do.

We used this unique opportunity to take a snapshot of the immune system’s genesis. For the first time in humans, we detected a group of jacks-of-all-trades, master-of-none immune cells, sometimes called virtual memory T cells, as a major part of the early immune system.”

Benjamin Youngblood, PhD, senior co-corresponding author, St. Jude Department of Immunology

Other scientists have found virtual memory T cells in model systems, but could not confirm the timeline of development in humans, leading to debate about their relevance. This is the first study to confirm the cell type’s existence in the earliest phase of human immune development, providing evidence of its importance.

Forming a bridge from the early immune system to long-term immunity

Typically, human immune cells are split into two groups, innate and adaptive. Innate cells act as the body’s first line of defense, reacting nonspecifically to infections and other threats. Adaptive cells provide long-term memory and immunity to specific infectious agents, but these cells take time to learn what is a threat. The virtual memory T cells did not fit into either group.

“We found that these virtual memory T cells had hallmarks of both innate and adaptive immunity,” said first author Anoop Babu Vasandan, PhD, St. Jude Department of Immunology. “These cells existed somewhere in the middle between them.” 

The researchers discovered that these cells had epigenetic and protein markers of both innate and adaptive cells. In functional tests, they reacted nonspecifically to immune signals of infectious threats, an innate-like reaction, while delivering an adaptive molecule, interferon-gamma, to neutralize them. These T cells’ existence between the two categories possibly provides a connection between fast-acting innate and long-lasting adaptive immunity before early immune memory forms.

“These virtual memory T cells are likely acting as a bridge until infants are out in the world and experiencing different infectious threats that educate their immune system,” said co-corresponding author Caitlin Zebley, MD, PhD, St. Department of Bone Marrow Transplantation & Cellular Therapy. “They allow the adaptive immune system time to undergo those first educational processes and develop true, rather than ‘virtual’ memory.”

While the study is the first to characterize these cells in early human immune development, much remains a mystery about this difficult-to-study cell type.

“Now we need to find ways to continue to study these virtual memory T cells and see if we can use them to improve childhood vaccinations or adapt them for other uses, such as immunotherapy,” Youngblood said. “We’ve only scratched the surface of understanding their potential.”

Authors and funding

The study’s other first and corresponding author is Hossam Abdelsamed, formerly of St. Jude. The study’s other authors are Shannon Boi, Grace Ward, Shanta Alli, Tian Mi, Xin Lan, Xusheng Zhang, Albert Zhou, Ewelina Mamcarz and Stephen Gottschalk, St. Jude; Xin Lan, University of Tennessee Health Science Center; Morton Cowan and Jennifer Puck, University of California San Francisco; and

Aleksandra Petrovic and David Rawlings, University of Washington.

The study was supported by grants from the National Institutes of Health (R01AI114442, R01CA237311, K08CA279926, P01HL053749, F32CA250155, U54AI082973 and P01AI138962), the ASSISI Foundation of Memphis, an Alex’s Lemonade Stand Foundation Young Investigator Grant, Stand Up To Cancer (SU2C), the Key for a Cure Foundation, the National Heart, Lung, and Blood Institute (NHLBI), the California Institute for Regenerative Medicine (CLIN2-10830 and CLIN2-09504) and ALSAC, the fundraising and awareness organization of St. Jude.