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Clonal expansion and development of immunological memory are two hallmarks of adaptive immune responses. Resolving the intricate pathways that regulate cell cycle activity and lead to the generation of diverse effector and memory T cell subsets is essential for improving our understanding of protective T cell immunity. A deeper knowledge of cell cycle regulation in T cells also has translational implications for adoptive cell therapies and vaccinations against infectious diseases. Here, we summarize recent evidence for an early diversification of effector and memory CD8+ T cell fates and discuss how this process is coupled to discrete changes in division speed. We further review technical advances in lineage tracing and cell cycle analysis and outline how these techniques have shed new light on the population dynamics of CD8+ T cell responses, thereby refining our current understanding of the developmental organization of the memory T cell pool. [ABSTRACT FROM AUTHOR]

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen‐specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self‐antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen‐specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single‐cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high‐affinity antigen‐specific CD8+ T cells are efficiently recruited upon systemic infection. In contrast, most low‐affinity antigen‐specific T cells ignore the priming antigen and persist in the naïve state while remaining fully responsive to subsequent immunization with a high‐affinity ligand. These data establish the widespread clonal ignorance of low‐affinity T cells as a major factor shaping the composition of antigen‐specific CD8+ T cell responses to systemic infection. [ABSTRACT FROM AUTHOR]

Rapid clonal expansion of antigen-specific T cells is a fundamental feature of adaptive immune responses. It enables the outgrowth of an individual T cell into thousands of clonal descendants that diversify into short-lived effectors and long-lived memory cells. Clonal expansion is thought to be programmed upon priming of a single naive T cell and then executed by homogenously fast divisions of all of its descendants. However, the actual speed of cell divisions in such an emerging “T cell family” has never been measured with single-cell resolution. Here, we utilize continuous livecell imaging in vitro to track the division speed and genealogical connections of all descendants derived from a single naive CD8+ T cell throughout up to ten divisions of activation-induced proliferation. This comprehensive mapping of T cell family trees identifies a short burst phase, in which division speed is homogenously fast and maintained independent of external cytokine availability or continued T cell receptor stimulation. Thereafter, however, division speed diversifies, and model-based computational analysis using a Bayesian inference framework for tree-structured data reveals a segregation into heritably fast- and slow-dividing branches. This diversification of division speed is preceded already during the burst phase by variable expression of the interleukin-2 receptor alpha chain. Later it is accompanied by selective expression of memory marker CD62L in slower dividing branches. Taken together, these data demonstrate that T cell clonal expansion is structured into subsequent burst and diversification phases, the latter of which coincides with specification of memory versus effector fate. [ABSTRACT FROM AUTHOR]