Asymmetric Cell Division in T Lymphocyte Fate Diversification

Immunological protection against microbial pathogens is dependent on robust generation of functionally diverse T lymphocyte subsets. Upon microbial infection, naïve CD4+ or CD8+ T lymphocytes can give rise to effector- and memory-fated progeny that together mediate a potent immune response. Recent advances in single-cell immunological and genomic profiling technologies have helped elucidate early and late diversification mechanisms that enable the generation of heterogeneity from single T lymphocytes. We discuss these findings here and argue that one such mechanism, asymmetric cell division, creates an early divergence in T lymphocyte fates by giving rise to daughter cells with a propensity towards the terminally differentiated effector or self-renewing memory lineages, with cell-intrinsic and -extrinsic cues from the microenvironment driving the final maturation steps.

TrendsRecent studies using limiting-dilution strategies or novel cell-tracing techniques have demonstrated that a single naïve CD4+ or CD8+ T lymphocyte can generate a heterogeneous adaptive immune response.Application of emerging single-cell technologies has revealed an early divergence of terminal effector and self-renewing memory lymphocyte fates that can only be observed at the single-cell level.Impaired asymmetric division at the initiation of the adaptive immune response reduces early molecular heterogeneity of CD8+ T lymphocytes, thus altering the balance of effector- and memory-fated precursor cells and reducing differentiation into the memory T lymphocyte fates.Single-cell approaches will be essential to improving our understanding of T lymphocyte fate determination and to advancing vaccination and therapeutic approaches that enhance long-term protective immune responses.