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

Sarah C. Edwards, Ann Hedley, Wilma H. M. Hoevenaar, Teresa Glauner, Robert Wiesheu, Anna Kilbey, Robin Shaw, Katerina Boufea, Nizar Batada, Karen Blyth, Crispin Miller, Kristina Kirschner, Seth B. Coffelt

Research output: Other contribution

Abstract / Description of output

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.
Original languageEnglish
PublisherbioRxiv
DOIs
Publication statusPublished - 2021

Fingerprint

Dive into the research topics of 'Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3'. Together they form a unique fingerprint.

Cite this