Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Lombès, Amélie; Durand, Aurélie; Charvet, Céline; Rivière, M; Bonilla, Nelly; Auffray, Cédric; Lucas, Bruno; Martin, Bruno

doi:10.4049/jimmunol.1500375

Cited by 43 publications

(52 citation statements)

References 58 publications

(59 reference statements)

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“…S6C). Furthermore, in agreement with published reports 45, 46 , we found that control IL-17 producing cells had a significantly higher CD44 MFI than IFNγ producing cells (Fig. S6D).…”

Section: Resultssupporting

confidence: 93%

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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“…S6C). Furthermore, in agreement with published reports 45, 46 , we found that control IL-17 producing cells had a significantly higher CD44 MFI than IFNγ producing cells (Fig. S6D).…”

Section: Resultssupporting

confidence: 93%

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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“…int gd27 + cells stimulated for 4 d with coated anti-CD3 and anti-CD28 mAb in the presence of IL-6, IL-23, and TGF-b1 were capable of differentiating into IL-17-producing gd T cells (70). We never observed IL-17 production from gd27 + cells upon stimulation with IL-1b plus IL-23, which was performed for 36 h and in absence of TCR engagement.…”

Section: Cd44mentioning

confidence: 59%

“…We never observed IL-17 production from gd27 + cells upon stimulation with IL-1b plus IL-23, which was performed for 36 h and in absence of TCR engagement. Moreover, the plasticity of gd27 + cells proposed by Lombes et al (70) remains to be observed during in vivo responses.…”

Section: Cd44mentioning

confidence: 89%

Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors

Barros‐Martins

Schmolka

Fontinha

et al. 2016

The Journal of Immunology

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γδ T lymphocytes are programmed into distinct IFN-γ–producing CD27+ (γδ27+) and IL-17–producing CD27− (γδ27−) subsets that play key roles in protective or pathogenic immune responses. Although the signature cytokines are shared with their αβ Th1 (for γδ27+) and Th17 (for γδ27−) cell counterparts, we dissect in this study similarities and differences in the transcriptional requirements of murine effector γδ27+, γδ27−CCR6−, and γδ27−CCR6+ γδ T cell subsets and αβ T cells. We found they share dependence on the master transcription factors T-bet and RORγt for IFN-γ and IL-17 production, respectively. However, Eomes is fully dispensable for IFN-γ production by γδ T cells. Furthermore, the Th17 cell auxiliary transcription factors RORα and BATF are not required for IL-17 production by γδ27− cell subsets. We also show that γδ27− (but not γδ27+) cells become polyfunctional upon IL-1β plus IL-23 stimulation, cosecreting IL-17A, IL-17F, IL-22, GM-CSF, and IFN-γ. Collectively, our in vitro and in vivo data firmly establish the molecular segregation between γδ27+ and γδ27− T cell subsets and provide novel insight on the nonoverlapping transcriptional networks that control the differentiation of effector γδ versus αβ T cell subsets.

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“…Because CD44 lo conventional gd T cells exhibit many similarities to naive ab T cells, we predict that they may require a combination of cytokines and tonic TCR signaling for homeostatic maintenance. This supposition is supported by a recent study that found similarities between gd T subsets and naive and memory CD8 + T cells (25). Using CD44 and Ly6C to divide gd T cells into subsets, the investigators found that the CD44 lo cells turn over slowly in the steady-state but convert to CD44 hi cells in a lymphopenic environment, much like naive CD8 + T cells.…”

Section: Discussionmentioning

confidence: 76%

Differential Responsiveness of Innate-like IL-17– and IFN-γ–Producing γδ T Cells to Homeostatic Cytokines

Corpuz

Stolp

Kim

et al. 2016

The Journal of Immunology

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γδ T cells respond to molecules upregulated following infection or cellular stress using both TCR and non-TCR molecules. The importance of innate signals versus TCR ligation varies greatly. Both innate-like IL-17–producing γδ T (γδT-17) and IFN-γ–producing γδ T (γδT-IFNγ) subsets tune the sensitivity of their TCR following thymic development, allowing robust responses to inflammatory cytokines in the periphery. The remaining conventional γδ T cells retain high TCR responsiveness. We determined homeostatic mechanisms that govern these various subsets in the peripheral lymphoid tissues. We found that, although innate-like γδT-17 and γδT-IFNγ cells share elements of thymic development, they diverge when it comes to homeostasis. Both exhibit acute sensitivity to cytokines compared with conventional γδ T cells, but they do not monopolize the same cytokine. γδT-17 cells rely exclusively on IL-7 for turnover and survival, aligning them with NKT17 cells; IL-7 ligation triggers proliferation, as well as promotes survival, upregulating Bcl-2 and Bcl-xL. γδT-IFNγ cells instead depend heavily on IL-15. They display traits analogous to memory CD8+ T cells and upregulate Bcl-xL and Mcl-1 upon cytokine stimulation. The conventional γδ T cells display low sensitivity to cytokine-alone stimulation and favor IL-7 for their turnover, characteristics reminiscent of naive αβ T cells, suggesting that they may also require tonic TCR signaling for population maintenance. These survival constraints suggest that γδ T cell subsets do not directly compete with each other for cytokines, but instead fall into resource niches with other functionally similar lymphocytes.

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Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Cited by 43 publications

References 58 publications

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

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

Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors

Differential Responsiveness of Innate-like IL-17– and IFN-γ–Producing γδ T Cells to Homeostatic Cytokines

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