T cell receptor signalling in γδ cell development: strength isn’t everything

Turchinovich, Gleb; Pennington, Daniel J.

doi:10.1016/j.it.2011.09.005

Cited by 44 publications

(50 citation statements)

References 64 publications

(128 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, we (19) and others (20,21) have shown that murine gd T cells acquire their effector properties during thymic development, in a process regulated by TCRgd (and coreceptor) signaling (22). For example, IFN-g-producing gd T cells require TCR and CD27 signals for differentiation in the mouse thymus (19)(20)(21).…”

mentioning

confidence: 89%

Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling

Ribot

Ribeiro

Correia

et al. 2014

The Journal of Immunology

109

View full text Add to dashboard Cite

Cytotoxicity and IFN-γ production by human γδ T cells underlie their potent antitumor functions. However, it remains unclear where and how human γδ T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine γδ T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo–isolated γδ thymocytes produced negligible IFN-γ and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.

show abstract

mentioning

confidence: 89%

Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling

Ribot

Ribeiro

Correia

et al. 2014

The Journal of Immunology

109

View full text Add to dashboard Cite

show abstract

“…We showed that robust IFN-γ production is associated with the CD27 (+) phenotype, whereas secretion of IL-17 is restricted to CD27 (−) γδ T cells. This dichotomy of hard-wired commitment to specific cytokine production is established during thymic development and maintained during the immune response to various infection agents (21,22). Thus, the overall impact of γδ T cells in a given disease may depend on the balance between distinct proinflammatory effector cell subsets.…”

Section: Significancementioning

confidence: 99%

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Rei

Gonçalves-Sousa

Lança

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

179

199

View full text Add to dashboard Cite

Cancer-associated inflammation mobilizes a variety of leukocyte populations that can inhibit or enhance tumor cell growth in situ. These subsets include γδ T cells, which can infiltrate tumors and typically provide large amounts of antitumor cytokines, such as IFN-γ. By contrast, we report here that in a well-established transplantable (ID8 cell line) model of peritoneal/ovarian cancer, γδ T cells promote tumor cell growth. γδ T cells accumulated in the peritoneal cavity in response to tumor challenge and could be visualized within solid tumor foci. Functional characterization of tumor-associated γδ T cells revealed preferential production of interleukin-17A (IL-17), rather than IFN-γ. Consistent with this finding, both T cell receptor (TCR)δ-deficient and IL-17-deficient mice displayed reduced ID8 tumor growth compared with wild-type animals. IL-17 production by γδ T cells in the tumor environment was essentially restricted to a highly proliferative CD27 (−) subset that expressed Vγ6 instead of the more common Vγ1 and Vγ4 TCR chains. The preferential expansion of IL-17-secreting CD27 (−) Vγ6 (+) γδ T cells associated with the selective mobilization of unconventional small peritoneal macrophages (SPMs) that, in comparison with large peritoneal macrophages, were enriched for IL-17 receptor A, and for protumor and proangiogenic molecular mediators, which were upregulated by IL-17. Importantly, SPMs were uniquely and directly capable of promoting ovarian cancer cell proliferation. Collectively, this work identifies an IL-17-dependent lymphoid/myeloid crosstalk involving γδ T cells and SPMs that promotes tumor cell growth and thus counteracts cancer immunosurveillance. gamma-delta T cells | tumor immunologyD eveloping tumors are infiltrated by a variety of leukocyte subsets that can either promote or inhibit inflammation, and thus impact on cancer progression (1). Among such populations are γδ T cells, which are major players in lymphoid stress surveillance likely due to their recognition of stress-inducible molecules independently of MHC-mediated antigen presentation (2). Moreover, abundant IFN-γ secretion and cytotoxic effector functions endow γδ T cells with potent antitumor activity. This has been clearly documented in murine models of spontaneous (3), chemically induced (4), transgenic (5), and transplantable (6, 7) tumors. For example, in the widely used B16 melanoma model, γδ T cells were shown to infiltrate tumors very early and provided a critical source of IFN-γ that significantly delayed tumor growth (6, 7).Human γδ T cells also possess IFN-γ-secreting potential, which is displayed immediately at birth (8) and display cytotoxicity against tumor lines of diverse origin, including epithelial (9, 10) and hematological (11,12) tumors. This has prompted the development of cancer clinical trials targeting γδ T cells, which have produced encouraging, albeit highly variable, degrees of therapeutic responses (13-15). There is therefore great interest in maximizing the antitumor functions of γδ T cells for cancer ...

show abstract

“…It has been proposed that γδTCR-ligand interaction determines the effector function of γδT cells (14). γδT cells that receive the ligand-dependent strong or ligandindependent weak γδTCR signals are induced to differentiate into IFN-γ-producing or IL-17-producing subsets, respectively (12,15). However, the molecular basis for this remains unclear.…”

Section: Introductionmentioning

confidence: 99%

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

Muro¹,

Nitta²,

Nakano³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

Results Preferential requirement of Syk rather than Zap70 in γδTCR signalsand γδT cell development. To characterize the intracellular signal γδT cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17-producing γδT (γδT17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of αβT cells, failed to functionally substitute for Syk in the development of γδT17. Syk induced the activation of the PI3K/Akt pathway upon γδTCR stimulation. Mice deficient in PI3K signaling exhibited a complete loss of γδT17, without impaired development of IFN-γ-producing γδT cells. Moreover, γδT17-dependent skin inflammation was ameliorated in mice deficient in RhoH, an adaptor known to recruit Syk. Thus, we deciphered lineage-specific TCR signaling and identified the Syk/PI3K pathway as a critical determinant of proinflammatory γδT cell differentiation.

show abstract

T cell receptor signalling in γδ cell development: strength isn’t everything

Cited by 44 publications

References 64 publications

Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling

Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

Contact Info

Product

Resources

About

T cell receptor signalling in γδ cell development: strength isn’t everything

Cited by 44 publications

References 64 publications

Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling

Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

Contact Info

Product

Resources

About

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages