TCR-inducible PLZF transcription factor required for innate phenotype of a subset of γδ T cells with restricted TCR diversity

Kreslavsky, Taras; Savage, Adam K.; Hobbs, Robin M.; Gounari, Fotini; Bronson, Roderick T.; Pereira, Pablo; Pandolfi, Pier Paolo; Bendelac, Albert; Boehmer, Harald von

doi:10.1073/pnas.0903895106

Cited by 236 publications

(307 citation statements)

References 38 publications

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“…Kisielow et al elegantly showed that SCART2, a marker for thymic IL-17A-producing gd T cells, is expressed in deviated DN thymocytes of ab TCRtransgenic mice, but again downregulated in negatively selecting male HY mice [20]. Likewise, Kreslavsky et al have recently shown that a strong TCR-signal can induce the transcription factor PLZF which is required for the developmental progress from immature IL-17A-producing into IFN-g and IL-4-producing innate effector gd T cells [44].…”

Section: Discussionmentioning

confidence: 99%

“…Along this line, we could clearly show that NK1.1 1 gd T cells were already in the thymus all CCR9 -. Therefore, our observation that a large shown that a strong TCR-signal can induce the transcription factor PLZF which is required for the developmental progress from immature IL-17A-producing into IFN-g and IL-4-producing innate effector gd T cells [44]. During the submission process of this manuscript, two groups have reported important additional information about IL-17A-producing gd T cells [45,46].…”

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confidence: 96%

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CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

et al. 2009

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cd T cells are a potent source of innate IL-17A and IFN-c, and they acquire the capacity to produce these cytokines within the thymus. However, the precise stages and required signals that guide this differentiation are unclear. Here we show that the CD24 low CD44 high effector cd T cells of the adult thymus are segregated into two lineages by the mutually exclusive expression of CCR6 and NK1.1. Only CCR6 1 cd T cells produced IL-17A, while NK1.1 1 cd T cells were efficient producers of IFN-c but not of IL-17A. Their effector phenotype correlated with loss of CCR9 expression, particularly among the NK1.1 1 cd T cells. Accordingly, both cd T-cell subsets were rare in gut-associated lymphoid tissues, but abundant in peripheral lymphoid tissues. There, they provided IL-17A and IFN-c in response to TCR-specific and TCR-independent stimuli. IL-12 and IL-18 induced IFN-c and IL-23 induced IL-17A production by NK1.1 1 or CCR6 1 cd T cells, respectively. Importantly, we show that CCR6 1 cd T cells are more responsive to TCR stimulation than their NK1.1 1 counterparts. In conclusion, our findings support the hypothesis that CCR6 1 IL-17A-producing cd T cells derive from less TCR-dependent selection events than IFN-c-producing NK1.1 1 cd T cells.Key words: gd T cells . CCR6 . IFN-g . IL-17A . Innate lymphocytes . NK1.1 Introduction IL-17A and IFN-g are generally regarded as pro-inflammatory effector cytokines that can be produced by Th cells but also by innate lymphocytes such as NK cells, NKT cells and gd T cells. While macrophage activation is supposed to be the main role of IFN-g, the induction of granulopoiesis is ascribed as a key biological function of IL-17A [1]. It is currently emerging that gd T cells are a potent source of IL-17A in the early phases of immune responses (reviewed in [2]). gd T cells constitute a large fraction of all IL-17A-producing cells in healthy mice and humans and are able to secrete IL-17A much more rapidly than CD4 1 Th17 cells [3][4][5]. These observations led to the concept that gd T cells are important players in a transitional response between innate and adaptive immune reactions [6]. The production of innate IL-17A by gd T cells appears to be essential in situations where an effective defence against extra-cellular bacteria or fungi relies on the fast mobilization of neutrophils [4,[6][7][8][9]. Moreover, IL-17A-producing gd T cells have been described to play important roles in immunopathologic diseases such as collageninduced arthritis [10], experimental pulmonary fibrosis [11], and in experimental autoimmune encephalitis [12,13].In contrast to CD4 1 Th cells that can develop into Th17 cells after encounter of specific cognate TCR Ag [14][15][16], it is not clear which stimuli induce IL-17A production by gd T cells in vivo. This essentially results from a lack of information about physiological gd TCR ligands. However, the current literature suggests that the decision whether a gd T cell will produce IL-17A is linked to 3488thymic development. Jensen et al. introduced a concept th...

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Section: Discussionmentioning

confidence: 99%

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confidence: 96%

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

et al. 2009

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“…These γδ NKT cells have innate properties and are able to secrete IL-4 ex vivo as shown in WT mice [47]. These data are reminiscent to TCR signaling mutant such as in Itk −/− [46], CD3ζ −/− [49], and SLP-76 [46] or LAT [50] mutant mice where the development of γδ NKT cells have been shown to be favored.…”

Section: Discussionmentioning

confidence: 88%

“…7A and B). PLZF expression in γδ T cells is largely restricted to the Vγ1.1 + Vδ6.3 + subset [46,47]. Intracellular staining of PLZF showed that the percentage of PLZF-expressing γδ T cells was increased in Dok-1 transgenic mice compared to WT mice ( Fig.…”

Section: Dok-1 Regulates the Development Of Sap-dependent Vγ11 + Vδ6mentioning

confidence: 99%

Dok‐1 overexpression promotes development of γδ natural killer T cells

et al. 2012

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In T cells, two members of the Dok family, Dok-1 and Dok-2, are predominantly expressed. Recent evidence suggests that they play a negative role in T-cell signaling. In order to define whether Dok proteins regulate T-cell development, we have generated transgenic mice overexpressing Dok-1 in thymocytes and peripheral T cells. We show that overexpression of Dok-1 retards the transition from the CD4 − CD8 − to CD4 + CD8 + stage. Moreover, there is a specific expansion of PLZF-expressing Vγ1.1 + Vδ6.3 + T cells. This subset of γδ T cells acquires innate characteristics including rapid IL-4 production following stimulation and requiring SLAM-associated adaptor protein (SAP) for their development. Moreover, Dok-1 overexpression promotes the generation of an innate-like CD8 + T-cell population that expresses Eomesodermin. Altogether, these findings identify a novel role for Dok-1 in the regulation of thymic differentiation and in particular, in the development of PLZF + γδ T cells.Keywords: γδ T cell r Dok r PLZF r SAP r Thymocyte development Supporting Information available online Introduction αβ T-lymphocyte development is dependent on productive rearrangement of the TCRβ locus and intracellular signaling initiated through the pre-TCR at the CD4 − CD8 − double-negative (DN) stage. Pre-TCR signaling leads to cellular proliferation and progression to the CD4 + CD8 + double-positive (DP) stage where TCRα locus rearrangement is induced. In DP thymocytes, initial TCR signal strength/duration will determine specific gene expression and Correspondence: Dr. Pascale Duplay e-mail: pascale.duplay@iaf.inrs.ca as a consequence will regulate the outcome of thymocyte positive versus negative selection and CD4 versus CD8 lineage differentiation or conventional versus innate lymphocyte lineage choice [1].γδ TCR lymphocytes also develop in the thymus and require productive rearrangement of the TCRγ and δ loci at the DN stage. The strength of TCR signaling is important in controlling αβ/γδ lineage choice. Strong TCR signaling is required for the commitment to the γδ lineage whereas weak TCR signals favor * These authors contributed equally to this work. Eur. J. Immunol. 2012Immunol. . 42: 2491Immunol. -2504 development of αβ lineage cells (reviewed in [2][3][4]). Moreover, TCR signal strength regulates also maturation and acquisition of effector functions in γδ and αβ T-cell development. Therefore, signaling molecules that modulate TCR signal strength play a pivotal role in the regulation of T-cell development and homeostasis. Development signals from the pre-TCR and from the TCR are controlled by the coordinated activity of tyrosine kinases such as Syk-family kinases [5], Src-family kinases [6], and Tec-family kinases [7,8] and adaptor molecules such as , LAT [10], Grb2 [11], and Gads [12].Dok are adaptor proteins that contain a pleckstrin homology domain, a phosphotyrosine binding domain, and a COOHterminal region containing multiple tyrosine phosphorylation sites [13,14]. Dok-1 and Dok-2, the two members of Dok family proteins e...

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“…[3][4][5][6][7][8][9][10] However, mechanisms of functional differentiation of effector cd T cells are poorly understood. [11][12][13][14] Key cytokines produced by cd T cells are interferon (IFN)-c, [15][16][17][18][19] tumor-necrosis factor (TNF)-a 20,21 and IL-17, [22][23][24][25][26] and are critical for pathogen clearance, immune regulation and autoimmunity. Shibata and colleagues reported that the basic helix-loop-helix protein HES1 is specifically expressed in IL-17 1 cd T cells and is required for the differentiation of naturally occurring IL-17 1 cd T cells in the thymus.…”

Section: Developmentmentioning

confidence: 99%

Current progress in γδ T-cell biology

Hao

Xia

et al. 2010

Cell Mol Immunol

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T lymphocytes bearing c-and d-chain T-cell receptor heterodimers are named cd T cells. Interestingly, cd and ab T cells share the same progenitors, and they undergo a fate decision in the thymus. Functional differentiation of cd T cells occurs both inside and outside the thymus. Antigen recognition of cd T-cell receptors is very unique, and the responses frequently exhibit innate characteristics. Nevertheless, peripheral cd T cells exert a number of effector and regulatory functions. cd T cells rapidly produce cytokines like interferon (IFN)-c and IL-17 and promote inflammation, partly due to the inherent epigenetic and transcriptional programs, which facilitates a quick and extensive response. Moreover, cd T cells lyse target cells directly, and this is necessary for pathogen or tumor clearance. cd T cells can even serve as regulatory cells, and may contribute to immune suppression. Orchestration of cd T-cell and other immune cell interactions may be critical for host defense and immune regulation. Recently, cd T cells have been used for immunotherapy for infectious diseases and malignancy. In this review, we summarize the abstracts presented at the recent cd T cell Conference held from 19 to 21 May 2010, in Kiel, Germany (please see the website for details: http://www.gammadeltaconference.uni-kiel.de/index.html). Peptide-major histocompatibility complex-specific T-cell responses are known to be achieved by ab T cells, while cd T-cell biology is much less studied. Mice without cd T cells are highly susceptible to diseases and tumor, suggesting an important role of cd T cells in defense. By current technology in cellular and molecular immunology, researchers revealed that cd T cells produce a series of cytokines in pathology, and the effector cd T cells play an indispensable role in pathogen elimination, immune regulation and autoimmunity. As a group of innate immune cells, cd T cells respond rapidly and expand efficiently when stimulated by antigens or cytokines. cd T cells may be a good target for modulation of immune responses in human diseases. In recent years, a lot of researchers focused on the cd T-cell development, function and therapeutic use.

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TCR-inducible PLZF transcription factor required for innate phenotype of a subset of γδ T cells with restricted TCR diversity

Cited by 236 publications

References 38 publications

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

Dok‐1 overexpression promotes development of γδ natural killer T cells

Current progress in γδ T-cell biology

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