The dimensions of human and murine CD8 T lymphocyte diversity

Abstract

The adaptive immune system generates and maintains a pool of CD8+ T cells with an almost limitless specificity with the purpose of maintaining homeostasis. Upon antigen encounter, CD8+ T cells undergo functional diversification and give rise to daughter cells. The daughter cells adopt one of many distinct states along a functional gradient from stem-like towards highly cytotoxic. After antigen clearance, a small fraction of antigen-experienced CD8+ T cells survives and constitutes a long-lived memory population that conveys long-term protection. The likelihood of a T cell acquiring or possessing the ability to maintain a long-term presence is related to the functional characteristics of that T cell during the active response phase. This thesis aims to unravel the biological dimensions underlying CD8+ T cell diversity and fate determination.

Recent developments in high dimensional proteome and transcriptome analysis revealed that antigen- experienced T cells form a continuum of functional states. This continuum is in contrast with the established subsetting into discrete subpopulations. We identified the chemokine receptor CX3CR1 as a graded, cross-species, pan T cell differentiation marker. CX3CR1 can be used to, in a convenient and simple manner, capture a principal component of T cell diversity. Furthermore, the CX3CR1 expression levels reflected similar functional states across species, enabling cross-species comparison of T cell properties. The enhanced insight into differentiation revealed that CX3CR1high CD8+ T cells uniquely patrol the luminal arteriolar surface. These CD8+ T cells scan the arteriolar surface for antigen, which supported their long-term survival. Finally, we unraveled T cell activation and proliferation as principal aspects of the T cell diversity in addition to differentiation. From this data, we constructed transcriptomic- and protein-based scores to provide a precise yet practical tool to identify and isolate differentiation and phase-specific CD8+ T cells.

In this thesis, we moved beyond binary classification of CD8+ T cell states and identified transcriptomic and functional gradients of CD8+ T cell diversity. These axes of diversity precisely described the position of individual CD8+ T cells within the T cell heterogeneity found in the effector and memory phase. By leveraging these axes, we identified markers and marker panels that easily, practically and precisely characterized CD8+ T cells.