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

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.

Spatially-resolved single cell transcriptomics reveal a critical role for γδ T cells in the control of skin inflammation and subcutaneous adipose wasting during chronicTrypanosoma bruceiinfection

“…After re-clustering, we identified a total of 1,043 cells encompassing Il5 + Gata3 + ILC2s (138 cells), Ncr1 + NK cells (172 cells), Icos + Rora + CD4 + T cells (426 cells), and two separate cell clusters of Trdc + gdT cells, 1 (155 cells) and 2 (152 cells) (Figure 4A and 4B). Both of the gd T cell clusters express high levels of Tcrg-C1, Cd163l1, but low levels of Cd27 (Figure 4B), and based on recent literature, this indicates that they are likely to be IL-17-producing Vg6 + cells 35 . In vivo, we observed a significant expansion of CD27 -(IL-17A-producing) gd T cells and a concomitant reduction in the frequency of CD27 + (IFNg-producing) gd T cells in skin biopsies from infected BALB/c mice compared to naïve controls (Figure 4C), following the same trend predicted by the scRNAseq data (Figure 4A and 4B), thus validating our in silico prediction.…”

Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment

“…Lack of VISTA expression also increased the expression of IL-17A in γδTh17 cells [ 205 ]. IL-17A is a proinflammatory factor that can induce γδT cells to express various ICRs [ 98 ] and IL-17A-producing γδT cells may instigate resistance to ICT [ 206 ]. Furthermore, blocking TIM-3 significantly increases the expression of IL-21R and negatively regulates the antitumor function of γδT cells by promoting the development of CD73+ γδT cells [ 169 ].…”

γδIL17 under control

“…The expansion of γδ17 cells after treatment with checkpoint inhibitors in this KB1P model may have important therapeutic implications. However, how the data presented by Edwards et al (2022) can be translated to the human setting is not clear. Indeed, mouse and human γ and δ loci are not conserved; for example, there are no clear homologues in human for the mouse Vγ4 and Vγ6 γδ17 subsets (Papadopoulou et al, 2020).…”

“…How these programmed γδIL17 cells are regulated in the periphery was not clear. Edwards et al (2022) addressed this question both under homeostatic and cancer conditions (see figure).…”