Invariant Natural Killer T Cell Subsets—More Than Just Developmental Intermediates

Krovi, S. Harsha; Gapin, Laurent

doi:10.3389/fimmu.2018.01393

Cited by 89 publications

(69 citation statements)

References 200 publications

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“…The "NK mid up" module is highly specific to NK cells during early EVD ( Figure 3A ) and is most enriched for "MARSON_BOUND_BY_FOXP3_STIMULATED" ( q = 0.0 71) and "BIOCARTA_CDC42RAC_PATHWAY" ( q = 0.08, Table S3 ). FOXP3 expression is characteristic of invariant NK cells (Engelmann et al, 2011) that secrete a wide variety of cytokines in response to stimulation (Krovi and Gapin, 2018) . The CDC42/RAC pathway is essential for the polarization of cytolytic granules in NK cells, a requirement for effective cytotoxicity (Sinai et al, 2010;Tybulewicz and Henderson, 2009) .…”

Section: Cell-type and Temporally-specific Modules Underlie Cell Statmentioning

confidence: 99%

Single-cell profiling of Ebola virus infectionin vivoreveals viral and host transcriptional dynamics

Kotliar

Lin

Logue

et al. 2020

Preprint

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Ebola virus (EBOV) causes epidemics with high case fatality rates, yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. To better understand EBOV infection in vivo , we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cell activity during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, providing insight into pathogenesis. We find that immature, proliferative monocyte-lineage cells with reduced antigen presentation capacity replace conventional circulating monocyte subsets within days of infection, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying viral RNA abundance in individual cells, we identify molecular determinants of tropism and examine temporal dynamics in viral and host gene expression. Within infected cells, we observe that EBOV down-regulates STAT1 mRNA and interferon signaling, and up-regulates putative pro-viral genes (e.g., DYNLL1 and HSPA5 ), nominating cellular pathways the virus manipulates for its replication. Overall, this study sheds light on EBOV tropism, replication dynamics, and elicited immune response, and provides a framework for characterizing interactions between hosts and emerging viruses in a maximum containment setting. over-activation of innate and adaptive immunity underlies much of EVD pathology, rather than solely virus-mediated cytotoxicity (Geisbert et al., 2003a(Geisbert et al., , 2003b .

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Section: Cell-type and Temporally-specific Modules Underlie Cell Statmentioning

confidence: 99%

Single-cell profiling of Ebola virus infectionin vivoreveals viral and host transcriptional dynamics

Kotliar

Lin

Logue

et al. 2020

Preprint

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“…Likewise, iNKT cells recognize glycolipid antigens presented by the non-polymorphic MHC class I-like molecule CD1d, through a single TRAV10/TRAJ18 alpha TCR and a restricted TCR-beta usage (8). These cells also appear to be important in tissue, and have been implicated in ameliorating or exacerbating a variety of diseases and illnesses, ranging from autoimmunity to cancer (9). In humans, MAIT cells compromise around 1-10% of peripheral blood T-cells whereas iNKT cells represent only ∼0.1% (10,11).…”

Section: Introductionmentioning

confidence: 99%

Unbiased Profiling Reveals Compartmentalization of Unconventional T-Cells Within the Intestinal Mucosa Irrespective of HIV Infection

et al. 2020

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The intestinal mucosa is enriched for unconventional T-cells, including mucosal associated invariant T-cells (MAIT), invariant natural killer T-cells (iNKT) and γδ T-cells. These cells are activated by bacterial metabolites, lipid antigens and cytokines, and are important for intestinal barrier integrity. The loss of gut homeostasis observed in HIV infection is central to disease pathogenesis, and studies have highlighted impairment of particular unconventional T-cell subsets within a specific gut compartment. However, although the small and large intestine are distinct niches, the overall impact of HIV on unconventional T-cells across the gut mucosal has not been well-studied. We hypothesized that compartment specific differences in the unconventional T-cell repertoire would exist between the small and large intestine, due to increasing bacterial loads and microbial diversity; and that the impact of HIV infection might differ depending on the compartment examined. We used mass cytometry, flow cytometry and unbiased T-cell receptor profiling to quantify unconventional T-cells in blood and tissue from the small (duodenum) and large (colon) intestine in HIV infected and uninfected participants undergoing examination for a range of intestinal conditions. Overall, we find distinct compartmentalisation of T-cells between blood, duodenum and colon, with iNKT cells significantly enriched in the duodenum and δ-1 expressing γδ T-cells in the colon. In addition, we observe greater clonal expansion of conventional TCRs in the duodenum, suggestive of stronger adaptive immunity in this compartment. Conversely, we find evidence of an expanded unconventional TCR repertoire in the colon, which contained far more overlapping "donor unrestricted" sequences than the duodenum. Twelve of these TCRs were highly "MAIT-like" and 3 were unique to the colon, suggesting an enrichment of donor unrestricted T-cells (DURTs) in this compartment. Unexpectedly, however, no Magnoumba et al. Unconventional T-Cells and HIV Infection significant impact of HIV infection on any of the unconventional T-cell subsets measured was observed in either mucosal site in terms of frequency or TCR repertoire. Further studies are required to investigate the importance of these unconventional T-cell subsets to intestinal homeostasis within the different gut compartments and determine if they are functionally impaired during HIV infection.

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“…While a large body of knowledge is available on iNKT cell characteristics and development in the thymus and in the periphery 12 , the developmental steps underlying iNKT cell differentiation, and by extension MAIT cells, remain, nevertheless, incomplete. In particular, studies have largely focused on analyzing iNKT cells in bulk, potentially missing developmental intermediate populations.…”

Section: Introductionmentioning

confidence: 99%

Single-cell RNA transcriptomics identifies Hivep3 as essential in regulating the development of innate-like T lymphocytes

Krovi

Zhang

Michaels-Foster

et al. 2020

Preprint

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Most T lymphocytes leave the thymus as naïve cells with limited functionality. However, unique populations of T cells, commonly known as innate-like T cells, differentiate into functionally distinct effector subsets during thymic development under the influence of the transcription factor PLZF. Here, we profiled >10,000 differentiating thymic iNKT cells using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of their maturation, function, and fate decision in steady state. We identified Hivep3, a zinc finger transcription factor and adaptor protein, as a key factor that is expressed in early precursors and regulates the postselection proliferative burst, differentiation and functions of iNKT cells. Importantly, we extended these results to other PLZF + innate-like T cell populations, highlighting the unique and common requirement of Hivep3 to the development of all innate-like T cells.

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Invariant Natural Killer T Cell Subsets—More Than Just Developmental Intermediates

Cited by 89 publications

References 200 publications

Single-cell profiling of Ebola virus infectionin vivoreveals viral and host transcriptional dynamics

Single-cell profiling of Ebola virus infectionin vivoreveals viral and host transcriptional dynamics

Unbiased Profiling Reveals Compartmentalization of Unconventional T-Cells Within the Intestinal Mucosa Irrespective of HIV Infection

Single-cell RNA transcriptomics identifies Hivep3 as essential in regulating the development of innate-like T lymphocytes

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