Understanding Heterogeneous Differentiation of CD8+ T Cells

The population-level patterns of T-cell response for an infection is highly reproducible. But the underlying single-cell behaviour for such reproducibility is not clearly known. The in vivo lineage tracing of CD8+ T-cells has been studied through two different experimental techniques, DNA barcoding[1] and immunological coding[2]. Observations from these studies demonstrate that expansion of identical CD8+ T Cells show heterogeneity in both clonal family sizes and marker distribution. Buchholz et al.[2] compared a number of different models and concluded that the data best supported a linear differentiation pathway: naive T-cell → TCM → TEMp → TEF, with proliferation rate increasing through the pathway. Whereas Gerlach et al.[1] conclude that asymmetric division by itself cannot explain the experimentally observed disparity between individual T-cell families, and further, they note there is a strong heterogeneity at the single-cell level indicating that T-cell response can be highly variable. Over this, invitro experimental evidence does not overwhelmingly support any single developmental pathway.

In order to reconcile these contradictory models of differentiation pathway, a population model that is devoid of the cellular types, but has only stochastically distributed markers is suggested. We propose a branching process for the proliferation of cells, with stochastically distributing inheritance factors that can approximate the observed behaviour. The branching process is augmented with the modified cyton model that has been defined in the context of B-cell expansion[3]. Three markers are assumed, which are stochastically inherited at each cell division, and have different rates of accumulation. The model replicates the experimental observations qualitatively. In the generalised branching process model, we have shown that two simple sub-cellular factors were required to maintain the frequency distribution of a population.

1) Gerlach et.al., Science 340, 635–639(2013). 2) Buchholz et.al., Science 340, 630–635(2013). 3) Markham et.al., J. of The Royal Society Interface 7, 1049–1059(2013).