Two distinct subpopulations of human stem-like memory T cells exhibit complementary roles in self-renewal and clonal longevity.

T stem cell-like memory cells (TSCM cells) are considered to be essential for the maintenance of immune memory. The TSCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed.

The impact of model assumptions in interpreting cell kinetic studies.

Stable isotope labelling is one of the best methods currently available for quantifying cell dynamics in vivo, particularly in humans where the absence of toxicity makes it preferable over other techniques such as CFSE or BrdU. Interpretation of stable isotope labelling data (as for BrdU and CFSE) necessitates simplifying assumptions. Here we investigate the impact of three of the most commonly used simplifying assumptions: (i) that the cell population of interest is closed, (ii) that the population of interest is kinetically homogeneous, and (iii) that the population is spatially homogeneous and suggest pragmatic ways in which the resulting errors can be reduced.

Proliferation makes a substantive contribution to the maintenance of airway resident memory T-cell subsets in young pigs.

Tissue-resident memory (TRM) T cells play an important role in protection against respiratory infection but whether this memory is maintained by long-lived or dividing cells remains controversial. To address the rate of division of lung TRM T cells, deuterium-enriched water was administered orally to young pigs to label dividing lymphocytes. T-cell subsets were separated from blood, lymph nodes, and airways [bronchoalveolar lavage (BAL)], the latter comprising almost exclusively TRM.

Deuterated water (HO, heavy water) labelling to investigate human cell dynamics - lessons in protocol design and toxicity from the current literature.

The use of deuterated water (also known as 'heavy water') as a tracer to measure human cell proliferation rates for specific cell subsets has expanded significantly in recent years. Although there have been several published methods papers, investigators developing new applications may be confused by differences in study design and deuterated water dose/duration. Furthermore, this approach may be met with regulatory difficulties and participant concerns about toxicity.

Absolute quantification of rare gene targets in limited samples using crude lysate and ddPCR.

Accurate quantification of rare genes from limited clinical samples is crucial for research purposes but is technically challenging, especially due to nucleic acid extraction. Using the commercially available genomic DNA (gDNA) extraction kits, which mostly include a DNA purification step through silica columns, magnetic beads or ethanol precipitation, are the preferred choice for many researchers. These kits, however, have a minimum cell number requirement for optimal DNA quality and yield.

Inhibitory KIRs decrease HLA class II-mediated protection in Type 1 Diabetes.

Inhibitory killer cell immunoglobulin-like receptors (iKIRs) are a family of inhibitory receptors that are expressed by natural killer (NK) cells and late-stage differentiated T cells. There is accumulating evidence that iKIRs regulate T cell-mediated immunity. Recently, we reported that T cell-mediated control was enhanced by iKIRs in chronic viral infections.

Germline natural killer cell receptors modulating the T cell response.

In addition to their central role during innate responses, NK cells regulate adaptive immunity through various mechanisms. A wide array of innate receptors has been involved in the NK cell regulatory function. However, the clinical implications of these regulatory pathways are poorly understood.

Innate receptors modulating adaptive T cell responses: KIR-HLA interactions and T cell-mediated control of chronic viral infections.

Killer-cell immunoglobulin-like receptors (KIRs) are mainly expressed on natural killer (NK) cells and are key regulators of innate immune responses. NK cells are the first responders in the face of infection and help promote placentation during pregnancy; the importance of KIRs in these NK-mediated processes is well-established. However, mounting evidence suggests that KIRs also have a prominent and long-lasting effect on the adaptive immune system.

Peripheral T cell lymphopenia in COVID-19: potential mechanisms and impact.

Immunopathogenesis involving T lymphocytes, which play a key role in defence against viral infection, could contribute to the spectrum of COVID-19 disease and provide an avenue for treatment. To address this question, a review of clinical observational studies and autopsy data in English and Chinese languages was conducted with a search of registered clinical trials. Peripheral lymphopenia affecting CD4 and CD8 T cells was a striking feature of severe COVID-19 compared with non-severe disease.

Identification of proliferative and non-proliferative subpopulations of leukemic cells in CLL.

Pathogenesis in chronic lymphocytic leukemia (CLL) is strongly linked to the potential for leukemic cells to migrate to and proliferate within lymph-nodes. Previous in vivo studies suggest that all leukemic cells participate in cycles of migration and proliferation. In vitro studies, however, have shown heterogeneous migration patterns.

CD57 Memory T Cells Proliferate In Vivo.

A central paradigm in the field of lymphocyte biology asserts that replicatively senescent memory T cells express the carbohydrate epitope CD57. These cells nonetheless accumulate with age and expand numerically in response to persistent antigenic stimulation. Here, we use in vivo deuterium labeling and ex vivo analyses of telomere length, telomerase activity, and intracellular expression of the cell-cycle marker Ki67 to distinguish between two non-exclusive scenarios: (1) CD57 memory T cells do not proliferate and instead arise via phenotypic transition from the CD57 memory T cell pool; and/or (2) CD57 memory T cells self-renew via intracompartmental proliferation.

The relative contributions of infectious and mitotic spread to HTLV-1 persistence.

Human T-lymphotropic virus type-1 (HTLV-1) persists within hosts via infectious spread (de novo infection) and mitotic spread (infected cell proliferation), creating a population structure of multiple clones (infected cell populations with identical genomic proviral integration sites). The relative contributions of infectious and mitotic spread to HTLV-1 persistence are unknown, and will determine the efficacy of different approaches to treatment. The prevailing view is that infectious spread is negligible in HTLV-1 persistence beyond early infection.

The Rules of Human T Cell Fate .

The processes governing lymphocyte fate (division, differentiation, and death), are typically assumed to be independent of cell age. This assumption has been challenged by a series of elegant studies which clearly show that, for murine cells , lymphocyte fate is age-dependent and that younger cells (i.e.

Identifying the immune interactions underlying HLA class I disease associations.

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8 T cell responses which are restricted by the host HLA class I allotype.

Current estimates of T cell kinetics in humans.

Stable isotope labeling is a generally applicable method of quantifying cell dynamics. Its advent has opened up the way for the quantitative study of T cells in humans. However, the literature is confusing as estimates vary by orders of magnitude between studies.

Inhibitory killer cell immunoglobulin-like receptors strengthen CD8 T cell-mediated control of HIV-1, HCV, and HTLV-1.

Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell-mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8 T cell survival.

Human TSCM cell dynamics in vivo are compatible with long-lived immunological memory and stemness.

Adaptive immunity relies on the generation and maintenance of memory T cells to provide protection against repeated antigen exposure. It has been hypothesised that a self-renewing population of T cells, named stem cell-like memory T (TSCM) cells, are responsible for maintaining memory. However, it is not clear if the dynamics of TSCM cells in vivo are compatible with this hypothesis.

Different Selected Mechanisms Attenuated the Inhibitory Interaction of KIR2DL1 with C2 HLA-C in Two Indigenous Human Populations in Southern Africa.

The functions of human NK cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell Ig-like receptors (KIRs) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide.

The fate and lifespan of human monocyte subsets in steady state and systemic inflammation.

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.

HIV-1 adaptation to NK cell-mediated immune pressure.

The observation, by Alter et al., of the enrichment of NK cell "escape" variants in individuals carrying certain Killer-cell Immunoglobulin-like Receptor (KIR) genes is compelling evidence that natural killer (NK) cells exert selection pressure on HIV-1. Alter et al hypothesise that variant peptide, in complex with HLA class I molecules binds KIR receptors and either increases NK cell inhibition or decreases NK cell activation compared to wild type peptide thus leading to virus escape from the NK cell response.

Physiologically Based Simulations of Deuterated Glucose for Quantifying Cell Turnover in Humans.

[6,6-H]-glucose labeling is a state-of-the-art technique for quantifying cell proliferation and cell disappearance in humans. However, there are discrepancies between estimates of T cell proliferation reported in short (1-day) versus long (7-day) H-glucose studies and very-long (9-week) HO studies. It has been suggested that these discrepancies arise from underestimation of true glucose exposure from intermittent blood sampling in the 1-day study.

Human T Cell Memory: A Dynamic View.

Long-term T cell-mediated protection depends upon the formation of a pool of memory cells to protect against future pathogen challenge. In this review we argue that looking at T cell memory from a dynamic viewpoint can help in understanding how memory populations are maintained following pathogen exposure or vaccination. For example, a dynamic view resolves the apparent paradox between the relatively short lifespans of individual memory cells and very long-lived immunological memory by focussing on the persistence of clonal populations, rather than individual cells.