CCR7 defines a precursor for murine iNKT cells in thymus and periphery

Wang, Haiguang; Hogquist, Kristin A.

doi:10.7554/elife.34793

Cited by 79 publications

(123 citation statements)

References 45 publications

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“…T CM also express CD62L and are found primarily in SLO and blood (28). Of note, some staining protocols and tissue processing experiments with these organs involve incubations at room temperature or 37˚C, such as peptide/MHC tetramer enrichment or staining of chemokine receptors (29)(30)(31). We observed that a considerable portion of T CM express high levels of both ARTC2.2 and P2RX7 (7) (Fig.…”

Section: Anti-artc22 Nanobody Blockade Preserves Cd62l Expression Inmentioning

confidence: 61%

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

Silva

Wang

Qian

et al. 2019

The Journal of Immunology

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Peripheral invariant NKT cells (iNKT) and CD8+ tissue-resident memory T cells (TRM) express high levels of the extracellular ATP receptor P2RX7 in mice. High extracellular ATP concentrations or NAD-mediated P2RX7 ribosylation by the enzyme ARTC2.2 can induce P2RX7 pore formation and cell death. Because both ATP and NAD are released during tissue preparation for analysis, cell death through these pathways may compromise the analysis of iNKT and CD8+ TRM. Indeed, ARTC2.2 blockade enhanced recovery of viable liver iNKT and TRM. The expression of ARTC2.2 and P2RX7 on distinct iNKT subsets and TRM is unclear, however, as is the impact of recovery from other nonlymphoid sites. In this study, we performed a comprehensive analysis of ARTC2.2 and P2RX7 expression in iNKT and CD8+ T cells in diverse tissues, at steady-state and after viral infection. NKT1 cells and CD8+ TRM express high levels of both ARTC2.2 and P2RX7 compared with NKT2, NKT17, and CD8+ circulating memory subsets. Using nanobody-mediated ARTC2.2 antagonism, we showed that ARTC2.2 blockade enhanced NKT1 and TRM recovery from nonlymphoid tissues during cell preparation. Moreover, blockade of this pathway was essential to preserve functionality, viability, and proliferation of both populations. We also showed that short-term direct P2RX7 blockade enhanced recovery of TRM, although to a lesser degree. In summary, our data show that short-term in vivo blockade of the ARTC2.2/P2RX7 axis permits much improved flow cytometry–based phenotyping and enumeration of murine iNKT and TRM from nonlymphoid tissues, and it represents a crucial step for functional studies of these populations.

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Section: Anti-artc22 Nanobody Blockade Preserves Cd62l Expression Inmentioning

confidence: 61%

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

Silva

Wang

Qian

et al. 2019

The Journal of Immunology

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“…This transition is accompanied by a strong induction of Plac8 and Ccr7 (Fig. 2d), in line 258 with their migration from the cortex to the medulla (Wang and Hogquist, 2018). Then, iNKT2a 259 appeared as a node that split into two branches leading to either iNKT17, as illustrated by Rorc 260 expression ( Fig.…”

mentioning

confidence: 83%

“…Comparative analysis between iNKT2a and iNKT2b 181 transcriptomes indicated that iNKT2a were enriched for genes related to tissue emigration such 182 as Klf2 and S100a4 (Weinreich and Hogquist, 2008) (Supplemental Table 3) that may indicate 183 the presence of potential iNKT thymic emigrants as recently proposed (Wang and Hogquist,184 2018). Ccr7 transcripts were also enriched in iNKT2a (Wang and Hogquist, 2018). Table 2).…”

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confidence: 97%

High dimensional single-cell analysis reveals iNKT cell developmental trajectories and effector fate decision

Baranek

Lebrigand

Herbozo

et al. 2020

Preprint

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transcriptome; FHL2. 25 26 Abbreviations: DEG, differentially-expressed gene; FHL2, Four-and-a-half LIM domain 2; 27 iNKT, invariant Natural Killer T cell; IL-, interleukin-; IFN, interferon; PAGA, partition-based 28 graph abstraction; TCR, T cell receptor; TF, transcription factor; WT, wild-type 29 30 31 32 33 34 2 Summary 35 CD1d-restricted invariant Natural Killer T (iNKT) cells represent a unique class of T 36 lymphocytes endowed with potent regulatory and effector immune functions. Although these 37 functions are acquired during thymic ontogeny, the sequence of events that give rise to discrete 38 effector subsets remains unclear. Using an unbiased single-cell transcriptomic analysis 39 combined with functional assays, we revealed an unappreciated diversity among thymic iNKT 40 cells, especially among iNKT1 cells. Mathematical modelling and biological methods 41 unravelled a developmental map whereby iNKT2 cells constitute a transient branching point 42 towards the generation of iNKT1 and iNKT17 cells, which reconciles the two previously 43 proposed models. In addition, we identified the transcription co-factor Four-and-a-half LIM 44 domains protein 2 (FHL2) as a critical cell-intrinsic regulator of iNKT1 specification. Thus, 45 these data illustrate the changing transcriptional network that guides iNKT cell effector fate. Type I or invariant (i) Natural Killer T (iNKT) cells are a versatile population of thymus-derived 70 αβT cells that play a critical role in the initiation and orchestration of immune responses in 71 many pathological contexts including infection, cancer, inflammation and metabolic disorders 72 (Bendelac et al., 2007; Godfrey et al., 2010). iNKT cells respond to lipid-based antigens 73 presented by the quasi-monomorphic MHC class I-related CD1d molecule (Bendelac et al., 74 2007). Their swift response in the periphery is largely dependent on the existence of discrete 75 pre-set subsets that secrete substantial amounts of either interleukin 4 (IL-4), IL-17A/F or 76 interferon-γ (IFN-γ) akin to MHC-restricted T-helper cells and innate lymphoid cells (ILCs). 77 This functional segregation is believed to be instigated in the thymus during their development 78 involving many cues such as self-antigen recognition, transcription factors (TF), cytokine 79 receptor signalling and cell-cell interactions. 80 The developmental steps underlying iNKT cell differentiation remain controversial. Two non-81 mutually exclusive models have been proposed. Initially, a linear maturation model has been 82 reported (Benlagha et al., 2002; Pellicci et al., 2002) in which newly-selected stage 0 (CD24 + ) 83 iNKT cells mature through stages 1 to 3 with the loss of CD24 expression and the sequential 84 acquisition of CD44 and NK1.1. Functionally, iNKT cell maturation through these stages is 85 associated with a reduced capacity to produce IL-4 and concomitant increase in IFN-γ 86 production, which implies that IL-4-producing iNKT cells (comprised in stage 2) constitute an 87 immature pool of cells. A more recent line...

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“…It is thus conceivable that the high expression of Styk1 in thymic NK1.1 + iNKT cells marks a population of thymus-resident iNKT cells, because previous work showed that only thymic NK1.1 − iNKT cells emigrate from the thymus to seed the peripheral iNKT cell pools [22,23]. Along this line, a recent study demonstrated that all thymic iNKT effector cells are long-term residents that do not emigrate [24]. In future studies, it will thus be interesting to investigate whether Styk1 expression indicates transcriptional signatures shared by NK cells and thymic Styk1 + NK1.1 + iNKT cells but not by ILCs and peripheral Styk1 -iNKT cells.…”

Section: Styk1 Is Highly Expressed In Thymic But Not In Peripheral αβmentioning

confidence: 99%

Styk1 is specifically expressed in NK1.1⁺ lymphocytes including NK, γδ T, and iNKT cells in mice, but is dispensable for their ontogeny and function

et al. 2019

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Innate T cells, NK cells, and innate‐like lymphocytes (ILCs) share transcriptional signatures that translate into overlapping developmental and functional programs. A prominent example for genes that are highly expressed in NK cells but not in ILCs is serine‐threonine‐tyrosine kinase 1 (Styk1 encoded by Styk1). We found Styk1 to be specifically expressed in lymphocytes positive for Killer cell lectin‐like receptor subfamily B, member 1, also known as CD161 or NK1.1, i.e. in NK cell, αβ iNKT, and γδ NKT cell lineages. To investigate the role of Styk1 in the development and function of NK1.1+ innate T‐cell subsets, we generated and analyzed a novel Styk1null mutant mouse line. Furthermore, we validated Styk1 expression in γδ NKT cells and in thymic, but not in peripheral invariant αβ iNKT cells through ex vivo analysis of a concomitantly generated transgenic Styk1 reporter mouse line. Despite the very specific expression of Styk1 in NK cells, γδ NKT cells, and thymic αβ iNKT, its absence did not alter homeostasis and function of these lineages. Thus, Styk1 expression is specific for NK cells and selected NK‐like innate T‐cell subsets, but dispensable for their development and function.

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CCR7 defines a precursor for murine iNKT cells in thymus and periphery

Cited by 79 publications

References 45 publications

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

High dimensional single-cell analysis reveals iNKT cell developmental trajectories and effector fate decision

Styk1 is specifically expressed in NK1.1⁺ lymphocytes including NK, γδ T, and iNKT cells in mice, but is dispensable for their ontogeny and function

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CCR7 defines a precursor for murine iNKT cells in thymus and periphery

Cited by 79 publications

References 45 publications

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

High dimensional single-cell analysis reveals iNKT cell developmental trajectories and effector fate decision

Styk1 is specifically expressed in NK1.1+ lymphocytes including NK, γδ T, and iNKT cells in mice, but is dispensable for their ontogeny and function

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Styk1 is specifically expressed in NK1.1⁺ lymphocytes including NK, γδ T, and iNKT cells in mice, but is dispensable for their ontogeny and function