Edwards, S. C. et al. (2023) PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A–producing γδ T cells. Journal of Experimental Medicine, 220(2), e20211431. (doi: 10.1084/jem.20211431) (PMID:36480166) (PMCID:PMC9732671)
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Abstract
IL-17A–producing γδ T cells in mice consist primarily of Vγ6+ tissue-resident cells and Vγ4+ circulating cells. How these γδ T cell subsets are regulated during homeostasis and cancer remains poorly understood. Using single-cell RNA sequencing and flow cytommetry, we show that lung Vγ4+ and Vγ6+ cells from tumor-free and tumor-bearing mice express contrasting cell surface molecules as well as distinct co-inhibitory molecules, which function to suppress their expansion. Vγ6+ cells express constitutively high levels of PD-1, whereas Vγ4+ cells upregulate TIM-3 in response to tumor-derived IL-1β and IL-23. Inhibition of either PD-1 or TIM-3 in mammary tumor–bearing mice increased Vγ6+ and Vγ4+ cell numbers, respectively. We found that genetic deletion of γδ T cells elicits responsiveness to anti–PD-1 and anti–TIM-3 immunotherapy in a mammary tumor model that is refractory to T cell checkpoint inhibitors, indicating that IL-17A–producing γδ T cells instigate resistance to immunotherapy. Together, these data demonstrate how lung IL-17A–producing γδ T cell subsets are differentially controlled by PD-1 and TIM-3 in steady-state and cancer.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Wiesheu, Robert and Kirschner, Dr Kristina and Coffelt, Professor Seth and Glauner, Teresa and Blyth, Professor Karen and Hoevenaar, Ms Wilma and Edwards, Dr Sarah and Miller, Professor Crispin and Kilbey, Dr Anna |
| Creator Roles: | Edwards, S. C.Conceptualization, Data curation, Formal analysis, Visualization, Writing – original draft, Writing – review and editing Hoevenaar, W. H.M.Data curation, Formal analysis, Visualization, Writing – review and editing Wiesheu, R.Data curation, Formal analysis, Visualization, Writing – review and editing Glauner, T.Data curation, Formal analysis, Visualization, Writing – review and editing Kilbey, A.Data curation, Formal analysis, Visualization, Writing – review and editing Blyth, K.Writing – review and editing, Supervision Miller, C.Writing – review and editing, Supervision Kirschner, K.Data curation, Formal analysis, Visualization, Writing – review and editing Coffelt, S. B.Conceptualization, Data curation, Visualization, Writing – original draft, Writing – review and editing, Supervision, Funding acquisition |
| Authors: | Edwards, S. C., Hedley, A., Hoevenaar, W. H.M., Wiesheu, R., Glauner, T., Kilbey, A., Shaw, R., Boufea, K., Batada, N., Hatano, S., Yoshikai, Y., Blyth, K., Miller, C., Kirschner, K., and Coffelt, S. B. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| Journal Name: | Journal of Experimental Medicine |
| Publisher: | Rockefeller University Press |
| ISSN: | 0022-1007 |
| ISSN (Online): | 1540-9538 |
| Published Online: | 07 December 2022 |
| Copyright Holders: | Copyright © 2022 Edwards et al. |
| First Published: | First published in Journal of Experimental Medicine 220(2): e20211431 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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