Two functionally distinct subsets of IL‐17 producing γδ T cells

O’Brien, Rebecca L.; Born, Willi K.

doi:10.1111/imr.12905

Cited by 26 publications

(31 citation statements)

References 152 publications

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“…IL-2c reduced the prevalence of Tγδ17 cells in orthotopic BC (figure 5G), which are known to segregate functionally into Vγ4 or Vγ6 populations in mice. 38 We found Vγ4 + cells to be the predominant Tγδ17 subtype in orthotopic MB49 BC (online supplemental figure S3A). Vγ4 chains commonly pair with Vδ4 34 and in IL-2c treated tumors, we found a significant reduction in Vγ4δ4 prevalence (figure 5H) and a trend to decreased numbers (online supplemental figure S3B).…”

Section: Il-2c Treatment Effects On γδ T Cells Are Tissue-specificmentioning

confidence: 76%

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

Reyes

Deng

Zhang

et al. 2021

J Immunother Cancer

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BackgroundAnti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+ antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+ mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.ResultsIL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+ T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+ T cells but not γδ T cells.ConclusionsMechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.

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Section: Il-2c Treatment Effects On γδ T Cells Are Tissue-specificmentioning

confidence: 76%

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

Reyes

Deng

Zhang

et al. 2021

J Immunother Cancer

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“…Mouse IL-17A-producing γδ T cells predominantly express Vγ4 or Vγ6 T cell receptor (TCR) chains (O’Brien and Born, 2020). In adult mice, Vγ4 + and Vγ6 + cells are self-renewing and persist for a long time in tissues (Sandrock et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Functionally, these two subsets are indistinguishable. Their phenotype is almost identical, but there are some differences in the molecules they express, their behavior and their distribution (O’Brien and Born, 2020). For example, the TCR repertoire for the Vγ6 population utilises an invariant clone with few semi-invariant clones for the Vγ6Vδ1 pairing (Sandrock et al, 2018; Wei et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3

Hedley

Whm

et al. 2021

Preprint

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IL-17A-producing γδ T cells within the lung consist of both Vγ6+ tissue-resident cells and Vγ4+ circulating cells that play important roles in homeostasis, inflammation, infection, tumor progression and metastasis. How these γδ T cell subsets are regulated in the lung environment during homeostasis and cancer remains poorly understood. Using single-cell RNA sequencing and flow cytometry, we show that lung Vγ6+ cells express a repertoire of cell surface molecules distinctive from Vγ4+ cells, including PD-1 and ICOS. We found that PD-1 functions as a co-inhibitory molecule on Vγ6+ cells to reduce IL-17A production, whereas manipulation of ICOS signaling fails to affect IL-17A in Vγ6+ cells. In a mammary tumor model, ICOS and PD-1 expression on lung Vγ6+ cells remained stable. However, Vγ6+ and Vγ4+ cells within the lung pre-metastatic niche increased expression of IL-17A, IL-17F, amphiregulin (AREG) and TIM-3 in response to tumor-derived IL-1β and IL-23, where the upregulation of TIM-3 was specific to Vγ4+ cells. Inhibition of either PD-1 or TIM-3 in mammary tumor-bearing mice further increased IL-17A by Vγ6+ and Vγ4+ cells, indicating that both PD-1 and TIM-3 function as negative regulators of IL-17A-producing γδ T cell subsets. Together, these data demonstrate how lung γδ T cell subsets are differentially controlled by co-inhibitory molecules in steady-state and cancer.

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“…The function of γδ T cells in PBC has not been well elucidated. Human γδ T cells display antiviral, proin ammatory or cytotoxic abilities in different liver and autoimmune diseases through the production of various cytokines, mainly IFN-γ, TNF-α, and GZMB [4,5,8,23]. In this study, we analyzed the expression of activation markers and functional molecules of both the TCRγδ high and TCRγδ low subsets in PBC patients and HCs.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Gamma-Delta T Cells in Patients With Primary Biliary Cholangitis

Chen

Sun

et al. 2021

Preprint

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Background & Aims Gamma-delta (γδ) T cells are involved in the development of diverse liver and autoimmune diseases, whereas the role of γδ T cells in primary biliary cholangitis (PBC) remains unclear. Methods We analyzed the number, phenotypes, and functional molecules of γδ T cells in PBC patients (n = 74) and sex- and age-matched healthy controls (HCs) (n = 74) by flow cytometric analysis. Results We identified two distinct functional subsets of circulating γδ T cells according to the CD3/TCRγδ complex: the TCRγδhigh and TCRγδlow subsets. Approximately three-quarters of cells in the TCRγδhigh subset were Vδ1 T cells, while Vδ2 T cells were enriched in the TCRγδlow subset in HCs. The frequency and absolute number of circulating TCRγδlow cells was significantly decreased in PBC patients compared with HCs (p < 0.001). Furthermore, the frequency of TCRγδlow cells was negatively correlated with disease severity and positively correlated with the ursodeoxycholic acid response. TCRγδlow cells exhibited a similar apoptotic and proliferative phenotype but enhanced liver-homing chemokine receptor (CXCR6) expression in PBC patients compared with HCs. In addition, both TCRγδhigh and TCRγδlow subsets were more activated in PBC compared with HCs, characterized by elevated expression levels of CD69 and HLA-DR. Finally, we found an increased granzyme B (GZMB) production and similar IFN-γ and TNF-α production of TCRγδlow cells in PBC patients compared with HCs. Conclusion The TCRγδlow subset might be a potential marker for disease progression and treatment response in PBC, which may play a crucial role in liver injury through increased CXCR6 expression and GZMB production.

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Two functionally distinct subsets of IL‐17 producing γδ T cells

Cited by 26 publications

References 152 publications

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3

Alterations in Gamma-Delta T Cells in Patients With Primary Biliary Cholangitis

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