Inhibitor of DNA Binding 3 Limits Development of Murine Slam-Associated Adaptor Protein-Dependent “Innate” γδ T cells

Verykokakis, Mihalis; Boos, Markus D.; Bendelac, Albert; Adams, Erin J.; Pereira, Pablo; Kee, Barbara L.

doi:10.1371/journal.pone.0009303

Cited by 83 publications

(107 citation statements)

References 64 publications

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“…Thus, a very small number of highly related sequences constitute .75% of the expressed Vd6.4 chains in Thy-1 dull gd T cells from DBA/2 mice (16). The same sequences were also found in the Vd6.3 chains expressed by Thy-1 dull gd T cells and by NK1.1 + gd T cells in the B6 background, albeit at lower frequencies (13,16,23). These sequences are characterized by a germline Dd2-Jd1 junction that leaves intact both gene segments and imposes a unique reading frame of the Dd2 and by a V-Dd2 junction with little trimming of the ends of the segments and limited N-nucleotide addition.…”

supporting

confidence: 61%

Critical Role of TCR Specificity in the Development of Vγ1Vδ6.3+ Innate NKTγδ Cells

Pereira

Berthault

Burlen-Defranoux

et al. 2013

The Journal of Immunology

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A large fraction of innate NKTγδ T cells uses TCRs composed of a semi-invariant Vδ6.3/6.4-Dδ2-Jδ1 chain together with more diverse Vγ1-Jγ4 chains. To address the role of γδTCR specificity in their generation, we analyzed their development in mice transgenic (Tg) for a Vγ1-Jγ4 chain frequently expressed by NKTγδ cells (Tg-γ) and in mice Tg for the same Vγ1-Jγ4 chain together with a Vδ6BDδ2Jδ1 chain not usually found among NKTγδ cells (Tg-γδ). Surprisingly, both promyelocytic leukemia zinc finger (PLZF)+ and NK1.1+ NKTγδ cells were found in the thymus of Tg-γδ albeit at lower numbers than in Tg-γ mice, and virtually all of them expressed the Tg TCR. However, the PLZF+ subset, but not the NK1.1+ subset, also expressed an endogenous Vδ6.3/6.4 chain, and its size was severely reduced in TCRδ−/− Tg-γδ mice. These results could suggest that the PLZF+ and the NK1.1+ subsets are developmentally unrelated. However, PLZF+ and NK1.1+ NKTγδ cells express identical Vδ6.3/6.4 chains, and NK1.1+ cells can be obtained upon intrathymic injection of sorted PLZF+ cells, thus indicating their developmental relationship. In fact, the NK1.1+ γδ thymocytes present in Tg-γδ mice correspond to a small subset of NK1.1+ γδ thymocytes in wild-type animals, which express a more diverse repertoire of TCRs and can be recognized by the expression of the CD62L Ag. Collectively, our data demonstrated that TCR specificity is essential for the development of most NKTγδ T cells and revealed a developmental heterogeneity in γδ T cells expressing the NK1.1 marker.

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confidence: 61%

Critical Role of TCR Specificity in the Development of Vγ1Vδ6.3+ Innate NKTγδ Cells

Pereira

Berthault

Burlen-Defranoux

et al. 2013

The Journal of Immunology

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“…2B). In contrast to recent studies, which reported an expansion of NKT cells expressing a γ/δ TCR in mice with mutations within proximal TCR signaling molecules or a lack of the transcription factor Id3 [55][56][57][58][59][60][61], we did not observe an accumulation of this rare NKT cell subset in slp-76 ace/ace mice (data not shown). Thus, besides NK cells [53] the slp-76-mutation specifically affects α/β-TCR + iNKT cells.…”

Section: Slpcontrasting

confidence: 99%

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

et al. 2016

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TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76 ace/ace mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP −/− iNKT cells, slp-76 ace/ace iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP −/− mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76 ace/ace mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.Keywords: ADAP r Cytokine r iNKT cell r Integrin r slp-76Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2016Immunol. . 46: 2121Immunol. -2136 Introduction iNKT cells express a panoply of NK-cell receptors [1] and a canonical TCR through which they recognize (glyco-)lipid antigens [2]. iNKT cells activate similar signaling cascades after TCR ligation like other T lymphocytes [3], but utilize unique transcription factors for their development such as the promyelocytic leukemia zinc finger (PLZF) [4][5][6]. According to two different developmental models PLZF characterizes distinct maturation stages and polarized subsets. The sequential lineage model suggests a gradual decrease of PLZFexpression following selection of iNKT cells which show a Th2-dominated cytokine profile during earlier and a Th1-dominated cytokine profile during later stages of intrathymic maturation [1,7]. The second model describes lineage diversification and simultaneous differentiation into Th1-, Th2-, or Th17-polarized subsets that are defined by the level of PLZF-expression [8]. Although many iNKT cells release both Th1 and Th2 cytokines on a single cell level [9], the production of IL-17 and IFN-γ is mutually exclusive within NK1.1 − cells [10][11][12]. Several transcription factors, such as Egr2, T-bet, ThPOK, Id2, Id3, and the Tec kinases Itk and Rlk have been implicated in the differentiation of iNKT cell subsets [6,8,[13][14][15][16][17] which home to distinct tissues. Specifically, liver and spleen constitute the main source for the Th1-polarized sublineage which is PLZF low . Th2-or ...

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“…In fact, Id3-null mice have increased generation of "innate-like" gd cells expressing TCR Vg1.1 Vd6.3 with limited junctional diversity. This gd T cell subset shares phenotypic and functional characteristics with ab NKT cells (27) and is repressed by Id3 (30,31). In line with a role of P2X7 activity in the ERK-Egr-Id3 signaling pathway, p2rx7 2/2 mice displayed increased peripheral representation of this cell subset, suggesting a role of extracellular ATP in modulating gd NKT cell development.…”

Section: Stimulation P2rx7mentioning

confidence: 67%

“…Although the ERK-Egr-Id3 signaling axis plays a role in gd lineage development, mice lacking Id3 display elevated numbers of gd T cells (26,30,31). In fact, Id3-null mice have increased generation of "innate-like" gd cells expressing TCR Vg1.1 Vd6.3 with limited junctional diversity.…”

Section: Stimulation P2rx7mentioning

confidence: 99%

Purinergic P2X7 Receptor Drives T Cell Lineage Choice and Shapes Peripheral γδ Cells

Frascoli¹,

Marcandalli²,

Schenk³

et al. 2012

The Journal of Immunology

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TCR signal strength instructs αβ versus γδ lineage decision in immature T cells. Increased signal strength of γδTCR with respect to pre-TCR results in induction of the γδ differentiation program. Extracellular ATP evokes physiological responses through purinergic P2 receptors expressed in the plasma membrane of virtually all cell types. In peripheral T cells, ATP released upon TCR stimulation enhances MAPK activation through P2X receptors. We investigated whether extracellular ATP and P2X receptors signaling tuned TCR signaling at the αβ/γδ lineage bifurcation checkpoint. We show that P2X7 expression was selectively increased in immature γδ+CD25+ cells. These cells were much more competent to release ATP than pre–TCR-expressing cells following TCR stimulation and Ca2+ influx. Genetic ablation as well as pharmacological antagonism of P2X7 resulted in impaired ERK phosphorylation, reduction of early growth response (Egr) transcripts induction, and diversion of γδTCR-expressing thymocytes toward the αβ lineage fate. The impairment of the ERK-Egr-inhibitor of differentiation 3 (Id3) signaling pathway in γδ cells from p2rx7−/− mice resulted in increased representation of the Id3-independent NK1.1-expressing γδ T cell subset in the periphery. Our results indicate that ATP release and P2X7 signaling upon γδTCR expression in immature thymocytes constitutes an important costimulus in T cell lineage choice through the ERK-Egr-Id3 signaling pathway and contributes to shaping the peripheral γδ T cell compartment.

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Inhibitor of DNA Binding 3 Limits Development of Murine Slam-Associated Adaptor Protein-Dependent “Innate” γδ T cells

Cited by 83 publications

References 64 publications

Critical Role of TCR Specificity in the Development of Vγ1Vδ6.3+ Innate NKTγδ Cells

Critical Role of TCR Specificity in the Development of Vγ1Vδ6.3+ Innate NKTγδ Cells

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

Purinergic P2X7 Receptor Drives T Cell Lineage Choice and Shapes Peripheral γδ Cells

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