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  • PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A-producing γδ T cells.

PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A-producing γδ T cells.

The Journal of experimental medicine (2022-12-09)
Sarah C Edwards, Ann Hedley, Wilma H M Hoevenaar, Robert Wiesheu, Teresa Glauner, Anna Kilbey, Robin Shaw, Katerina Boufea, Nizar Batada, Shinya Hatano, Yasunobu Yoshikai, Karen Blyth, Crispin Miller, Kristina Kirschner, Seth B Coffelt
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Anti-Rabbit IgG (H+L), Biotin antibody produced in goat, ~2 mg/mL, affinity isolated antibody