Our immune system is divided into two main branches: innate and adaptive. Innate immune cells act as a first line of defense, quickly responding to invaders, while adaptive immune cells take a longer time to respond but take a more targeted and robust defense. In between these two branches, there lies a subset of immune cells known as innate-like T cells. Innate-like T cells contain characteristics of both innate and adaptive immunity, which make them potential candidates for developing new immunotherapies against diseases such as cancer. However, the mechanisms and developmental pathways of innate-like T cells in humans are not fully understood. Now, researchers from Cold Spring Harbor Laboratory (CSHL) and the University of Colorado Anschutz sought to uncover the mysteries of these cells. Their findings reveal differences in how innate-like T cells mature in humans and mice, with age playing a critical role.
The study is published in Cell Reports in an article titled, “Unraveling the phenotypic states of human innate-like T cells: Comparative insights with conventional T cells and mouse models,” and led by CSHL assistant professor Hannah Meyer, PhD, and her collaborator Laurent Gapin, PhD, professor at the University of Colorado Anschutz.
“The ‘innate-like’ T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity,” the researchers wrote. “We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells display an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways.”
“Studying the development of the immune system is as important as investigating its role in disease,” explained Salomé Carcy, a former graduate student in the Meyer lab who co-led this study. “We need to understand immune cells’ origin to gain insights into their functional potential in pathological contexts. One of the key motivations of our work was to investigate how much our knowledge built on mouse models applies to human physiology.”
Using single-cell genomics and flow cytometry, the researchers discovered that innate-like T cells mature differently in humans than in mice, and that age plays a critical role. They observed that early in life, most innate-like T cells in the human thymus aren’t able to use all of their immune abilities. In adults’ bloodstreams, however, innate-like T cells are on standby, ready to fight as soon as they receive a signal. This pattern is observed in both mice and humans.
According to Meyer, these distinctions should make for key considerations when it comes to developing and testing immunotherapeutics, especially since much preclinical trial research is conducted in mouse models. “We need to take these differences into account,” Meyer said. “We’d be interested to look at these differences to see how they change over time and if these cells are more powerful at different ages. And is this something we can therapeutically exploit?”
Meyer and her team continue to dissect the complicated lives of immune system agents such as innate-like T cells. The findings pave the way for future research and may help to advance immunotherapies.
