Interleukin-17-Producing γδ T Cells Originate from SOX13+ Progenitors that Are Independent of γδTCR Signaling

Spidale, Nicholas A.; Sylvia, Katelyn; Narayan, Kavitha; Miu, Bing; Frascoli, Michela; Melichar, Heather J.; Wu, Zhihao; Kisielow, Jan; Palin, Amy; Serwold, Thomas; Love, Paul E.; Kobayashi, Michihiro; Yoshimoto, Momoko; Jain, Nitya; Kang, Joonsoo

doi:10.1016/j.immuni.2018.09.010

Cited by 77 publications

(113 citation statements)

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“… T cell development is dependent on a characteristic subset of transcription factors including SOX4, SOX13, Blk, c-maf, HEB, and PLZF, among others (27,28,45,(52)(53)(54). Recently, it was reported that at least some T17 programming results from a SOX13-dominated transcriptional hard-wiring of early thymocyte precursors (29). These SOX13 progenitors appear to give rise to IL-17-producing V4, but not V6 cells.…”

Section: Discussionmentioning

confidence: 99%

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Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

Dienz

DeVault

Musial

et al. 2019

Preprint

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During thymic development,  T cells commit to either an IFN--or an IL-17-producing phenotype through mechanisms that remain unclear. Here, we investigated whether the SLAM/SAP signaling pathway played a role in the functional programming of thymic  T cells.Characterization of SLAM family receptor expression revealed that thymic  T cell subsets were each marked by distinct co-expression profiles of SLAMF1, SLAMF4, and SLAMF6. In the thymus, immature CD24 hi V1 and V4  T cells were largely contained within a SLAMF1 + SLAMF6 + double positive (DP) population, while mature CD24 low subsets were either SLAMF1 + or SLAMF6 + single positive (SP) cells. In the periphery, SLAMF1 and SLAMF6 expression on V1, V4, and V6T cells distinguished IL-17-and IFN--producing subsets, respectively. Disruption of SLAM family receptor signaling through deletion of SAP resulted in impaired thymic  T cell maturation at the CD24 hi SLAMF1 + SLAMF6 + DP stage that was associated with a decreased frequency of CD44 + RORt +  T cells. These defects were in turn associated with impaired  T cell IL-17 and IFN- production in both the thymus as well as in peripheral tissues. The role for SAP was subset-specific, as V1, V4, V5, but not V6 subsets were SAP-dependent. Together, these data suggest that the SLAM/SAP signaling pathway regulates a critical checkpoint in the functional programming of IL-17 and IFN--producing T cell subsets during thymic development.3 Introduction:Innate-like γδ T cells are unusual T cells that are highly enriched in skin and mucosal tissues where they constitute a prominent source of cytokines and chemokines (1). In mice, most  T cells produce either IL-17 or IFN-γ, and IL-17 production is primarily restricted to the CD27 -CCR6 + V4 and V6 subsets (Heilig and Tonegawa nomenclature (2)), whereas IFN- production is observed in CD27 + CCR6 -V1, V4, V5, and V7 subsets (3-6). Accumulating data suggest that the relative balance of these IL-17 or IFN-γ-producing subsets can have significant consequences on disease outcome. IFN--producing  T cells, for example, contribute to anti-tumor immunity (7) and inflammation in a model of cerebral malaria (3,8). IL-17-producing γδ T cells, in contrast, have been associated with protection against bacterial and fungal infections (9-11), and promotion of tumor metastasis (12, 13) and immunopathologies in settings of autoimmunity (14-19).Like their innate-like T cell counterparts, iNKT cells and MAIT cells, the functional programming of innate-like  T cells occurs during thymic development. Unlike iNKT and MAIT cells, however, a significant portion of  T cell developmental programming is restricted to a discrete developmental window (20), as it has been demonstrated that most natural IL-17producing  T cells (T17) are generated only during the embryonic/early post-natal stage (21). Although the mechanisms that regulate the differentiation of  T cells into IFN- or IL-17producing subsets remain unclear, a significant body of data supports a ...

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Section: Discussionmentioning

confidence: 99%

“…hardwired transcriptional programs (27)(28)(29). Exactly how these seemingly independent mechanisms converge to regulate the developmental programming of innate-like  T cell subsets remains an open question.…”

mentioning

confidence: 99%

Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

Dienz

DeVault

Musial

et al. 2019

Preprint

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“…As the origin of progenitors during development may be linked to the generation of distinct populations within the immune system, we revisited the controversial origin of the first wave of TSP. By analogy with the documented YS origin of tissue resident macrophages (Gomez Perdiguero et al, 2015b;Perdiguero and Geissmann, 2016), it was proposed that also early developing innate-like T cells and therefore the first TSP were HSC independent (Böiers et al, 2013;Gentek et al, 2018a;Kobayashi et al, 2014;Luis et al, 2016;Spidale et al, 2018;Yoshimoto et al, 2011Yoshimoto et al, , 2012.…”

Section: Disscusionmentioning

confidence: 98%

“…They expressed lymphoid associated genes (Il7r, Rag2, Rag1) and were proposed as the origin of the first wave of TSP (Luis et al, 2016). Independent reports have also converged to support the notion that Vg5 + and another gd T cell subset, Vg6 + IL-17 producing might originate from YS progenitors, independent of HSCs (Gentek et al, 2018a;Spidale et al, 2018). In contrast to the above studies, Vg5 + and B1a B cells were shown to be preferentially derived from a particular HSC-like subset, transiently found in the FL but not in the adult BM, marked by an history of Flk2 expression (Beaudin et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A wave of embryonic bipotent T/lymphoid tissue inducer progenitors regulates the maturation of medullary thymic epithelial cells

Elsaid

Meunier

Burlen-Defranoux

et al. 2019

Preprint

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Multiple waves of hematopoietic progenitors with distinct lineage potentials are differentially regulated in time and space. The site of origin and the cellular outputs of the first wave of thymic seeding progenitors remain unclear. Here we show that these progenitors are T/ILC restricted and unique in generating lymphoid tissue inducer cells, in addition to embryonic-derived invariant Vg5 + gdT cells that are both essential for the development of thymic medullary cells and thus shape the thymic architecture. We further show that all lymphoid progenitors are exclusively of hematopoietic stem cell origin, despite the temporal overlap between thymopoiesis initiation and the transient expression of lymphoid transcripts in yolk sac precursors. This early transient expression does not alter their strict erythro-myeloid differentiation potential. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets required for the establishment of a functionally diverse immune system.3

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“…Although T cell receptor (TCR) signaling is necessary for γδT17 cell development (Wencker et al, 2014), experimental evidence based on hypomorphic CD3 mice and anti-CD3/TCR antibody administration suggested that only weak TCR signals are required (Munoz-Ruiz et al, 2016; Sumaria et al, 2017). In addition, a recent study showed that TCR signaling is not important for lineage specification but for transition into the early immature stage (Spidale et al, 2018). γδT17 cell generation is restricted to the embryonic and neonatal thymus (Haas et al, 2012) with the bone marrow displaying low capacity to produce these cells (Cai et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

The neonatal microenvironment programs conventional and intestinal Tbet⁺γδT17 cells through the transcription factor STAT5

Kadekar

Agerholm

Rizk

et al. 2019

Preprint

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15Interleukin(IL)-17-producing RORγt + γδ T (γδT17) cells develop in the embryonic thymus and 16 participate in type 3 immune responses. Herein we show that γδT17 cells rapidly proliferate within 17 neonatal lymph nodes and gut, where upon entry they uniquely upregulate Tbet and co-express IL-18 17, IL-22 and interferon(IFN) γ in a STAT3 and retinoic acid dependent manner. Neonatal 19 expansion was halted in mice conditionally deficient in STAT5 and its loss resulted in γδT17 cell 20 depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A 21 homologue had a dominant role over STAT5B in promoting γδT17 cell expansion and 22 downregulating gut-associated Tbet. In contrast, STAT5B preferentially expanded IFNγ-producing 23 γδ populations. Importantly, mice lacking γδT17 cells due to STAT5 deficiency displayed a 24 profound resistance to experimental autoimmune encephalomyelitis. Our data identify for the first 25 time STAT5 as a key molecular checkpoint allowing γδT17 cells to pass through a critical neonatal 26 developmental window to acquire tissue-specific characteristics essential for infection and 27 autoimmunity.28 subtypes, such as hepatosplenic T cell lymphoma (Nicolae et al., 2014), monomorphic 81 epitheliotropic intestinal T cell lymphoma (Kucuk et al., 2015; Nairismagi et al., 2016) and primary 82 cutaneous γδ T cell lymphoma (Kucuk et al., 2015). Notably, approximately 20% of identified 83 N642H mutations occur in γδ T cell derived lymphomas (de Araujo ED, 2019).84 4Herein, we show that STAT5 is critically required for the progression and expansion of γδT17 85 cells through neonatal life in the intestine and periphery. We provide evidence that intestinal γδT17 86 cells upregulate Tbet upon entry into the lamina propria after birth and co-express the cytokines IL-87 17, IL-22 and IFNγ in a mechanism dependent on STAT3 and retinoic acid. Furthermore, loss of 88 γδT17 cells due to STAT5 deficiency results in resistance to experimental autoimmune 89 encephalomyelitis in adult mice. Importantly, we show that STAT5A promotes γδT17 cell 90 expansion and downregulates intestinal Tbet favoring a type 17 program, whereas STAT5B favors 91 IFNγ-producing γδ populations and increases intestinal Tbet expression. Collectively, our data 92 suggest that neonatal life is a critical window of development and tissue specification for γδT17 93 cells, and that this process is tightly regulated by STAT5. 94 95 Results 96 STAT5 regulates the neonatal expansion of γδT17 cells 97 In order to test the importance of STAT5 in RORγt expressing γδ T cells, we crossed RORγt-Cre 98 mice (Eberl and Littman, 2004) with mice floxed for both STAT5a and STAT5b (RORγt CRE -99

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Interleukin-17-Producing γδ T Cells Originate from SOX13+ Progenitors that Are Independent of γδTCR Signaling

Cited by 77 publications

References 64 publications

Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

A wave of embryonic bipotent T/lymphoid tissue inducer progenitors regulates the maturation of medullary thymic epithelial cells

The neonatal microenvironment programs conventional and intestinal Tbet⁺γδT17 cells through the transcription factor STAT5

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Interleukin-17-Producing γδ T Cells Originate from SOX13+ Progenitors that Are Independent of γδTCR Signaling

Cited by 77 publications

References 64 publications

Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

A wave of embryonic bipotent T/lymphoid tissue inducer progenitors regulates the maturation of medullary thymic epithelial cells

The neonatal microenvironment programs conventional and intestinal Tbet+γδT17 cells through the transcription factor STAT5

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The neonatal microenvironment programs conventional and intestinal Tbet⁺γδT17 cells through the transcription factor STAT5