Skint-1 is a highly specific, unique selecting component for epidermal T cells

Barbee, Susannah D.; Woodward, Martin J.; Turchinovich, Gleb; Mention, Jean–Jacques; Lewis, Julia M.; Boyden, Lynn M.; Lifton, Richard P.; Tigelaar, Robert E.; Hayday, Adrian

doi:10.1073/pnas.1010890108

Cited by 140 publications

(167 citation statements)

References 33 publications

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“…44,45 The restricted but mandatory implication of CD277 in the activation of particular human ␥␦ T-cell subsets brings to mind the mandatory role played by Skint-1, another member of the extended B7 receptor family, in the selection of murine intraepidermal ␥␦ T cells. [16][17][18] Although Skint-1 deficiency prevents differentiation of T cells expressing invariant V␥5V␦1 TCR, it has no effect on other ␥␦ or ␣␤ T-cell compartments. Whether Skint-1 directly interacts with V␥5V␦1 TCR or modulates TCR engagement by yet undefined antigens remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The mandatory role played by Skint-1 in the intrathymic positive selection and functional maturation of the murine intraepidermal V␥5V␦1 T-cell subset raises questions about the general role played by Skint1-related receptors in the selection and activation of ␥␦ T cells in mice and other species. [16][17][18][19] Although there are 10 intact skint1 paralogs in the mouse, the only human skint1 ortholog is a pseudogene. The human proteins with the greatest similarity to the extracellular domain of murine Skint-1 are the BTNs.…”

Section: Introductionmentioning

confidence: 99%

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Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Harly

Guillaume

Nédellec

et al. 2012

Blood

470

632

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Introduction␥␦ T cells are key players in the immune surveillance of cellular distress, thanks to their ability to recognize conserved determinants up-regulated after inflammation, infection, or cell transformation. 1,2 Although ␥␦ T-cell receptors (TCRs) contribute to detection of danger-associated determinants, ligands for these receptors have been identified in a few cases only. 3 Thus, the antigenic specificity of ␥␦ T cells and their fine activation modalities in response to cell stress remain largely unknown.One of the best studied ␥␦ T-cell subsets in humans expresses V␥9V␦2 TCR and predominates in blood, composing several percent of the whole peripheral lymphoid pool in most adults. V␥9V␦2 T cells are activated by nonpeptidic phosphorylated isoprenoid pathway metabolites, 4-6 hereafter referred to as phosphoagonists (PAg). Natural V␥9V␦2-stimulating PAg include isopentenyl pyrophosphate (IPP), 7 a metabolite of the mevalonate pathway found in mammalian cells and the desoxyxylulose phosphate pathway shared by many microorganisms, and hydroxy-methyl-butyl-pyrophosphate, 8 an intermediate of the latter pathway. PAg detection by ␥␦ T cells underlies their broad reactivity toward infected and transformed cells. Indeed, tumor cell recognition by V␥9V␦2 T cells is linked to enhanced production of the weak agonist IPP, resulting from increased cell metabolism and cholesterol biosynthesis. Accordingly, pharmacologic inhibitors of the mevalonate pathway that up-regulate (eg, aminobisphosphonates, NBP) or down-regulate (eg, statins) IPP production, respectively, increase or decrease antitumor V␥9V␦2 T-cell responses. 9,10 Moreover, because of the high V␥9V␦2 T cell-stimulating activity of the microbial agonist hydroxy-methyl-butyl-pyrophosphate, V␥9V␦2 T-cell responses are elicited by infected cells producing even traces of this PAg. 8 Although PAg-induced activation is restricted to V␥9V␦2 T cells and can be conferred by V␥9V␦2 TCR gene transfer, 11,12 attempts to detect cognate interactions between PAg and V␥9V␦2 TCR have failed so far. 13 So how V␥9V␦2 T cells sense PAg remains an enigma. PAg rapidly induce Ca 2ϩ signaling and activation of V␥9V␦2 T-cell clones, but this requires cell-to-cell contact, suggesting the implication of additional target cell surface receptors in this phenomenon. 11,14 PAg elicit V␥9V␦2 T-cell responses against basically all human cells, irrespective of their tissue origin, but do not induce recognition of any murine target cells. Therefore, the putative target cell receptors involved in PAg-mediated T-cell activation are expected to be broadly expressed by human, but not murine, cells.Activation of antigen-stimulated T cells is tuned by interactions involving T cell-derived CD28-related receptors and target cellderived B7-related counter-receptors, 15 which family includes members, such as Skint and butyrophilin (BTN) receptors. The mandatory role played by Skint-1 in the intrathymic positive There is an Inside Blood commentary on this article in this issue.The online version of this...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Harly

Guillaume

Nédellec

et al. 2012

Blood

470

632

View full text Add to dashboard Cite

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“…Initial reports suggested that antigen experienced γδ T cells, which had received ligand-dependent TCR signals, mature as IFNγ producers, while antigen naïve cells differentiate towards the γδ17 lineage 9 . Furthermore, in the past decade, there have been several reports debating the importance of different degrees of TCR signaling in the generation of γδ17 cells 10–13 . The signal strength hypothesis asserts that the quantity of the signal downstream of the TCR can direct lineage choice 8 .…”

Section: Introductionmentioning

confidence: 99%

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Zarin

Chen

et al. 2018

Immunol Cell Biol

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γδ T-cells perform a wide range of tissue and disease specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2−/− T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNγ versus IL-17 producing γδ T cell subsets, with Notch and weak TCR ligands optimally enabling development of γδ17 cells in the presence of IL-1β, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of γδ17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNγ and IL-17 producing γδ T-cell subsets.

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“…This 2-D assay is easy to perform, highly efficient and sensitive, allowing analysis at the single cell level. However, it neither supports T cell development beyond the stage of DP nor the generation of γδ DETC 13 , both of which require direct interactions with the thymic epithelium.…”

Section: Representative Resultsmentioning

confidence: 99%

Characterization of Thymic Settling Progenitors in the Mouse Embryo Using <em>In Vivo</em> and <em>In Vitro</em> Assays

Ramond

Bandeira

Berthault

et al. 2015

JoVE

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Characterizing thymic settling progenitors is important to understand the pre-thymic stages of T cell development, essential to devise strategies for T cell replacement in lymphopenic patients. We studied thymic settling progenitors from murine embryonic day 13 and 18 thymi by two complementary in vitro and in vivo techniques, both based on the "hanging drop" method. This method allowed colonizing irradiated fetal thymic lobes with E13 and/or E18 thymic progenitors distinguished by CD45 allotypic markers and thus following their progeny. Colonization with mixed populations allows analyzing cell autonomous differences in biologic properties of the progenitors while colonization with either population removes possible competitive selective pressures. The colonized thymic lobes can also be grafted in immunodeficient male recipient mice allowing the analysis of the mature T cell progeny in vivo, such as population dynamics of the peripheral immune system and colonization of different tissues and organs. Fetal thymic organ cultures revealed that E13 progenitors developed rapidly into all mature CD3 + cells and gave rise to the canonical γδ T cell subset, known as dendritic epithelial T cells. In comparison, E18 progenitors have a delayed differentiation and were unable to generate dendritic epithelial T cells. The monitoring of peripheral blood of thymus-grafted CD3 -/-mice further showed that E18 thymic settling progenitors generate, with time, larger numbers of mature T cells than their E13 counterparts, a feature that could not be appreciated in the short term fetal thymic organ cultures. Video LinkThe video component of this article can be found at

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Skint-1 is a highly specific, unique selecting component for epidermal T cells

Cited by 140 publications

References 33 publications

Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Characterization of Thymic Settling Progenitors in the Mouse Embryo Using <em>In Vivo</em> and <em>In Vitro</em> Assays

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