Stochastic Inheritance of Division and Death Times Determines the Size and Phenotype of CD8+ T Cell Families

Abstract

After antigen stimulation cognate naïve CD8+ T cells undergo rapid proliferation and ultimately their progeny differentiates into short-lived effectors and longer-lived memory T cells. Although the expansion of individual cells is very heterogeneous, the kinetics are reproducible at the level of the total population of cognate cells. After the expansion phase, the population contracts, and if antigen is cleared, a population of memory T cells remains behind. Different markers like CD62L, CD27, and KLRG1 have been used to define several T cell subsets (or cell fates) developing from individual naïve CD8+ T cells during the expansion phase. Growing evidence from high-throughput experiments, like single cell RNA sequencing, epigenetic profiling, and lineage tracing, highlights the need to model this differentiation process at the level of single cells. We model CD8+ T cell proliferation and differentiation as a competitive process between the division and death probabilities of individual cells (like in the Cyton model). We use an extended form of the Cyton model in which daughter cells inherit the division and death times from their mother cell in a stochastic manner (using lognormal distributions). We show that this stochastic model reproduces the dynamics of CD8+ T cells both at the population and at the single cell level. Modeling the expression of the CD62L, CD27, and KLRG1 markers of each individual cell, we find agreement with the changing phenotypic distributions of these markers in single cell RNA sequencing data. Retrospectively re-defining conventional T-cell subsets by "gating" on these markers, we find agreement with published population data, without having to assume that these subsets have different properties, i.e., correspond to different fates.