Intricate beginnings: Exploring human naive T cell heterogeneity

Abstract

Naive CD4+ 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 this thesis, we explored heterogeneity in the human naive T cell population across different ages, tissues and clinical settings. In Chapter 2 we identified a unique transcriptional naive T cell profile in the intestine compared to blood with signs of increased sensitivity for activation. We found that this profile was partially shared across ages, but was most pronounced in the fetal intestine. In addition, we found extensive memory differentiation in the fetal intestine, with TCR characteristics indicating a shared developmental origin rather than strong clonal expansion. Together with increased frequencies of gut-homing naïve T cells with activation-prone features in blood in early life, these findings could imply that early life naïve T cells are developmentally primed for intestinal migration and local differentiation. In Chapter 3, we described the T cell population in breastmilk, which was composed of memory T cells, with high proliferation and a more Th1/cytotoxic profile compared to blood. In addition, we identified a strong regulatory component and increased tissue homing and tissue-residency markers. We hypothesized that the breastmilk T cell profile might reflect breast tissue adaptation. In Chapter 4, we show that CD31-CD31 interactions can decrease TCR activation threshold in CD31+ naive T cells. We find no proof for specific CD31-mediated inhibition nor for TCR-mediated CD31 downregulation , in contrast to what earlier literature hypothesized. In Chapter 5, we studied immune reconstitution following autologous hematopoietic stem cell transplantation (aHSCT) in severe Crohn’s disease patients. We observed a strong and long-lasting reduction in the naïve/memory and CD4+/CD8+ T cell ratio, but found that this effect was less pronounced in non-responders. We found no proof for accelerated naive T cell turnover during lymphopenia nor for accelerated naive T cell differentiation. Overall, changes in T cell composition were more pronounced than changes in functional markers. In Chapter 6, we found that the naive T cell compartment in the majority of young adult thymectomized (Tx) individuals had normalized compared to age-matched controls, potentially due to regained thymic output. However, in a subset of non-normalized Tx individuals and older individuals, we found reduced naive T cell frequencies and recent thymic emigrants (RTE), as well as an enhanced ‘activated’ RTE-profile. We found no changes in TCR diversity of naïve nor memory T cells in Tx, no increase in immunosenescence, but did identify a more differentiated cytokine production profile in non-normalized Tx and older individuals.