Scientists solve 18-year-old mystery and find once-elusive source of critical T-cell population

One of the most rigorous debates in immunology has centered on the origin of an enigmatic population of T cells that possess memory-conferring and stem cell-like qualities, but the facts about their genesis were so elusive that debate raged for nearly two decades over the source. of these vital constituents of the immune system.

Now, Swiss scientists have identified precursor cells known as stem-like central memory T cells (TCM cells) and tracked their transformation from precursors to active players in the immune response. The cells themselves were first identified in 2005.

Since then, immunologists have been searching for the origin of stem-like central memory T cells. Early evidence suggested that it may have been a subset of CD8.⁺ T cells, widely known interchangeably as cytotoxic or killer T cells. These immune system warriors are known for their defense against pathogens and their relentless 24-hour surveillance for cancer cells.

To be clear, the existence of MTC cells was not part of the years-long mystery because immunologists can quickly identify them when they see them. Stem-like central memory T cells (TCM cells) are critical to the ability of the adaptive immune system to create lasting memories by commandeering pathogens during episodes of infection or re-exposure, and triggering rapid mobilization of vital defense of the host. Adaptive immunity is dominated by T cells and B cells. This type of immunity develops over time, as opposed to innate immunity, the nonspecific immune response that reacts from birth.

What remained unknown was the origin of MTC cells. Immunologists had long wondered whether these stem-like T cells were actually killer T cells that acquired the properties of memory T cells. Although essential to the overall immune response, MTC cells were deeply mired in debate and controversy as immunologists around the world argued over the cells’ source of origin.

Questions persisted: Were they relatively rare, emerging only in the face of mass infection? Were these unique cells that developed alongside the killer Ts? Nobody was sure.

Although scientists hypothesize that MTC cells are also key players in the response to vaccination, filling in the gaps regarding the genesis of these cells has remained stubbornly elusive, at least until now. New research now describes when these cells form during the immune response.

The study, reported in Scientific immunology, sheds light on these cells, and scientists at the University of Lausanne tracked the emergence of stem cell-like central memory T cells in an animal model. The team also found that when laboratory animals were confronted with a viral infection, TCM cells rapidly emerged. By solving the mystery of the cell’s origin, scientists discovered that the cells are indeed derived from CD8.⁺ Killer T – Ts cells.

“In response to infection, naive CD8⁺ T cells produce a large pool of short-lived terminal effector cells that eliminate infected host cells,” writes Joana Gomes Silva, lead author of the new research. “In parallel, a minor population of stem cell-like central memory cells forms, which has the capacity to maintain immunity after the elimination of pathogens. »

Silva noted that it remained unclear whether stem-like TCM cells arose from dedifferentiation of a subset of T-terminal cytolytic effector cells or whether priming generated stem-like cells capable of seeding the TCM . Dedifferentiation is a transient process by which cells become less specialized and revert to a previous cellular state within the same lineage.

The Swiss team, which included research conducted at the Translational Data Science Facility at the Swiss Institute of Bioinformatics, also in Lausanne, discovered that several subtle but rapid steps led to the coveted MTC cells. In the study, Silva and colleagues described how a group of central memory precursor T cells – TpCM cells – transformed into TCM cells in laboratory mice upon initial infection with lymphocytic choriomeningitis virus .

TpCM cells were detected early after infection and remained evident throughout the acute phase of the immune response. The important lesson from the research is that these precursors – TpCM cells – were predestined to become the TCM population, although they could also transform into effector T cells when exposed to inflammatory signals. Additionally, the ability to generate precursors in response to certain vaccination patterns, the team found, illustrates their immune memory and suggests the key role they could play in vaccines that target them.

The team discovered that early in the immune response to infection, precursors use the transcription factor TCF1, which predestines them to become the TCM population, while other CD8⁺ T cells diversify into other roles in response to inflammatory signals.

“A key goal of understanding the developmental origin of MTC cells is to generate such cells by vaccination. The identification of MTC precursor cells represents an important step toward this goal,” Silva concluded.

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