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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalThe Journal of experimental medicine
Issue number2
Publication statusPublished - Feb 6 2023

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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