Naive T cells are often described as the immune system’s blank slate: inexperienced cells waiting quietly until they encounter a virus, bacterium or other threat. The PhD project by UMC Utrecht researcher Elise Saager shows that this picture is too simplistic. Naive T cells can already differ depending on where they reside in the body as well as the age of the person. At the same time, they prove remarkably resilient when the immune system is severely disrupted. These findings provide new insights into immune development, vaccination, ageing and inflammatory disease.
T cells are an essential part of the adaptive immune system. Each newly formed, or ‘naive’, T cell carries a unique receptor that enables it to recognize a particular target. Once activated, it can multiply and develop into specialized effector and memory cells. This immune memory is one of the principles behind long-term protection after infection or vaccination.
Naive T cells stand at the basis of the adaptive immune system and can orchestrate a wide diversity of immune responses upon activation. Between their exit from the thymus and the moment of antigen-driven activation, naive T cells are presumed to maintain complete quiescence in order to preserve their full, ‘pristine’ potential. However, what if the various smaller, ‘non-antigenic’ triggers that are encountered throughout their course of life would already influence the naive T cell state? And are all naive T cells created equal?
In her PhD thesis, Elise Saager, MSc (Center for Translational Immunology, UMC Utrecht) examined whether the traditional textbook view of naïve T cells as a largely uniform population that remains in a resting state until needed holds true across different ages, tissues and conditions.
One of the clearest differences from textbook knowledge emerged in the intestine, particularly early in life. By studying T cells from fetal, childhood and adult intestinal tissue and comparing them with T cells in the blood, Saager and colleagues found that intestinal naive T cells were still genuinely ‘naive’, but had a distinct gut-associated profile. They showed signs of being more prepared for activation, especially before birth. Early-life naive T cells in the blood were also more likely to carry molecules that help them migrate towards the gut.
This finding may be important because the intestine suddenly encounters enormous numbers of microbes and new food components after birth. An immune system that is already prepared to respond, while learning what should and should not be tolerated, could provide an important head start. These findings may eventually help explain why immune responses, including responses to oral vaccines, vary with age and environment. However, this link still requires further research.
Saager and co-workers also investigated CD31, a molecule found on many naive T cells that becomes less common with age. Laboratory experiments showed that CD31 can lower the amount of stimulation required to activate a naive T cell. Cells carrying CD31 may therefore respond more easily when an immune signal is relatively weak.
This could potentially influence responses to infections and vaccines later in life, although the clinical relevance still needs to be established.
Other parts of the thesis showed how robust the T-cell system can be. In patients with severe, treatment-resistant Crohn’s disease undergoing autologous stem cell transplantation, the balance between different T-cell populations changed dramatically. These changes were strongest in patients who responded to treatment, whereas changes in the functional properties of the cells themselves were relatively limited.
Saager also studied young adults whose thymus had been removed during heart surgery early in childhood. Because the thymus produces new T cells, she investigated whether these people showed signs of prematurely aged immunity. In most participants, however, the T-cell population had largely recovered: its diversity and functional characteristics remained remarkably well preserved.
Elise Saager concludes: “Our findings show that naive T cells are neither identical blank slates nor cells that easily lose their original characteristics. Their location, age and developmental history can subtly influence how ready they are to respond, while the T-cell system as a whole is remarkably resilient. Better understanding these differences could ultimately help explain why responses to infection, vaccination and inflammatory disease vary across the lifespan.”
Elise S. Saager, PhD (1996, Amsterdam) defended her PhD thesis on October 26, 2026 at Utrecht University. The thesis is titled “Intricate beginnings: Exploring human naïve T cell heterogeneity.” Supervisors were Prof. Femke van Wijk, PhD (Center for Translational Immunology, UMC Utrecht) and Prof. Bas Oldenburg, MD PhD (Department of Gastroenterology, UMC Utrecht). Elise works as a postdoc at the CaixaResearch Institute in Barcelona (Spain) where she investigates early life immune development with a focus on improving childhood vaccinations in low-income settings.
