Heterogeneity is a hallmark feature of the adaptive immune system in vertebrates. Following infection, naive T cells differentiate into various subsets of effector and memory T cells, which help to eliminate pathogens and maintain long-term immunity. The current model suggests there is a single lineage of naive T cells that give rise to different populations of effector and memory T cells depending on the type and amounts of stimulation they encounter during infection. Here, we have discovered that multiple sub-populations of cells exist in the naive CD8 T cell pool that are distinguished by their developmental origin, unique transcriptional profiles, distinct chromatin landscapes, and different kinetics and phenotypes after microbial challenge. These data demonstrate that the naive CD8 T cell pool is not as homogeneous as previously thought and offers a new framework for explaining the remarkable heterogeneity in the effector and memory T cell subsets that arise after infection.

Recent work to characterize the roles of lipid segregation in IgE receptor signaling has revealed a mechanism by which segregation of liquid ordered regions from disordered regions of the plasma membrane results in protection of the Src family kinase Lyn from inactivating dephosphorylation by a transmembrane tyrosine phosphatase. Antigen-mediated crosslinking of IgE receptors drives their association with the liquid ordered regions, commonly called lipid rafts, and this facilitates receptor phosphorylation by active Lyn in the raft environment. Previous work showed that the membrane skeleton coupled to F-actin regulates stimulated receptor phosphorylation and downstream signaling processes, and more recent work implicates cytoskeletal interactions with ordered lipid rafts in this regulation. These and other results provide an emerging view of the complex role of membrane structure in orchestrating signal transduction mediated by immune and other cell surface receptors.

During the ontogeny of the mammalian immune system, distinct lineages of cells arise from fetal and adult hematopoietic stem cells (HSCs) during specific stages of development. However, in some cases, the same immune cell type is produced by both HSC populations, resulting in the generation of phenotypically similar cells with distinct origins and divergent functional properties. In this report, we demonstrate that neonatal CD8 T cells preferentially become short-lived effectors and adult CD8 T cells selectively form long-lived memory cells after infection because they are derived from distinct progenitor cells. Notably, we find that naïve neonatal CD8 T cells originate from a progenitor cell that is distinguished by expression of Lin28b. Remarkably, ectopic expression of Lin28b enables adult progenitors to give rise to CD8 T cells that are phenotypically and functionally analogous to those found in neonates. These findings suggest that neonatal and adult CD8 T cells belong to separate lineages of CD8 T cells, and potentially explain why it is challenging to elicit memory CD8 T cells in early life.

Neonates often generate incomplete immunity against intracellular pathogens, although the mechanism of this defect is poorly understood. An important question is whether the impaired development of memory CD8+ T cells in neonates is due to an immature priming environment or lymphocyte-intrinsic defects. Here we show that neonatal and adult CD8+ T cells adopted different fates when responding to equal amounts of stimulation in the same host. While adult CD8+ T cells differentiated into a heterogeneous pool of effector and memory cells, neonatal CD8+ T cells preferentially gave rise to short-lived effector cells and exhibited a distinct gene expression profile. Surprisingly, impaired neonatal memory formation was not due to a lack of responsiveness, but instead because neonatal CD8+ T cells expanded more rapidly than adult cells and quickly became terminally differentiated. Collectively, these findings demonstrate that neonatal CD8+ T cells exhibit an imbalance in effector and memory CD8+ T cell differentiation, which impairs the formation of memory CD8+ T cells in early life.

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Mobilization of Ca2+ in response to IgE receptor-mediated signaling is a key process in many aspects of mast cell function. Here we summarize our current understanding of the molecular bases for this process and the roles that it plays in physiologically relevant mast cell biology. Activation of IgE receptor signaling by antigen that crosslinks these complexes initiates Ca2+ mobilization as a fast wave that is frequently followed by a series of Ca2+ oscillations which are dependent on Ca2+ influx-mediated by coupling of the endoplasmic reticulum luminal Ca2+ sensor STIM1 to the calcium release activated calcium channel protein Orai1. Granule exocytosis depends on this process, together with the activation of protein kinase C isoforms, and specific roles for these signaling steps are beginning to be understood. Ca2+ mobilization also plays important roles in stimulated exocytosis of recycling endosomes and newly synthesized cytokines, as well as in antigen-mediated chemotaxis of rat mucosal mast cells. Phosphoinositide metabolism plays key roles in all of these processes, and we highlight these roles in several cases.

Accumulating evidence indicates that the immune system does not develop in a linear fashion, but rather as distinct developmental layers formed from sequential waves of hematopoietic stem cells, each giving rise to unique populations of immune cells at different stages of development. Although recent studies have indicated that conventional CD8+T cells produced in early life persist into adulthood and exhibit distinct roles during infection, the developmental architecture of the peripheral T cell compartment remains undefined. In this study, we used a mouse model to permanently label CD8+T cells produced during distinct windows of development and traced their history to generate fate maps of CD8+T cells produced during different stages of life. We then used mathematical modeling to understand the age structure of the CD8+T cell compartment across the lifespan. Interestingly, we found that survival rate of CD8+T cells depends on both the age and developmental origin of the cells. Recently produced cells show an initial rapid decay rate, which slows with age of the animal at which the cells were produced. For cells produced at any age, the rate of decay also slows with the age of the cell. We derive a function to describe this and predict the “age distribution” of the CD8+T cell pool for animals of any given age. These data provide a quantitative framework for understanding the ontogeny of the CD8+T cell compartment and help to contextualize age-related changes in the CD8+T cell response to infection.

MicroRNAs regulate most mammalian genes, and they control numerous aspects of immune system development and function. Their precise roles in the CD8+ T cell response, however, remain unclear. In this report, we show that in the absence of the microRNA miR-150, CD8+ T cells fail to undergo robust expansion and differentiation into short-lived terminal effector cells in response to primary infection with Listeria monocytogenes or Vaccinia virus. Notably, even after transitioning into the memory pool, miR-150−/− cells still mount a weaker recall response to secondary infection, and remain less differentiated than their wild-type counterparts. Transcriptome analysis shows miR-150 gene targets are globally upregulated in cells lacking miR-150, and amongst these targets, we found misregulation of genes associated with proliferation and effector cell function. These transcriptome data suggest that miR-150 deficient CD8+ T cells are less efficient in killing infected cells, which we validate experimentally. Together, these results reveal a cell-intrinsic role for miR-150 in the regulation of effector CD8+ T cell fate and function.