The important contributions of γδ T cells to immunity at barrier surfaces are well-established, but now Kohlgruber et al. report that γδ T cells have vital roles in immune homeostasis and thermogenesis in adipose tissues.

Credit: Simon Bradbrook/Macmillan Publishers Limited

First, the authors found that γδ T cells are abundant in various visceral adipose depots in mice, whereas they are less abundant in other organs (for example, the lungs, liver and spleen). In addition, parabiosis experiments in mice and flow cytometry analysis of human omentum demonstrated that γδ T cells are long-lived residents of adipose tissue.

The authors found that adipose-tissue-resident γδ T cells can be differentiated into two populations based on their expression levels of promyelocytic leukaemia zinc finger protein (PLZF), a transcription factor that is known to induce innate-like characteristics in some lymphocytes (such as invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells). Innate-like PLZF+ γδ T cells represent the majority (two-thirds) of γδ T cells in adipose tissue and produce tumour necrosis factor (TNF) and IL-17A, whereas PLZF– γδ T cells mostly produce interferon-γ (IFNγ). Importantly, the combination of TNF and IL-17A (but not either alone) produced by PLZF+ γδ T cells induced the production of IL-33 by adipose stromal cells in mice and in primary human preadipocytes; IL-33 is known to have an important role in non-shivering thermogenesis, a metabolic adaptation to cold temperatures.

a new, crucial role for γδ T cells in thermogenic responses in adipose tissues

Kohlgruber et al. then demonstrated that adipose-tissue-resident γδ T cells and IL-17A are important for regulatory T (Treg) cell homeostasis in adipose tissue. Treg cells are known to accumulate in adipose tissue in 20-week-old mice, which is mirrored by γδ T cells. Importantly, this accumulation of Treg cells was absent in TCRδ-deficient (Tcrd–/–) mice that lack γδ T cells. In addition, in Il17a–/– mice or mice deficient for two T cell receptor-γ genes (Vg4–/–Vg6–/– mice, which lack IL-17A-producing γδ T cells), Treg cells expressing the IL-33 receptor ST2 were specifically depleted in adipose tissue, but not in the lungs or spleen.

Next, the authors examined the physiological roles of γδ T cells and IL-17A in adipose tissue. Interestingly, in Tcrd–/– mice and Vg4–/–Vg6–/– mice, IL-33 protein and mRNA levels were lower in two adipose depots that are important for thermogenesis, namely brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT), respectively, than in wild-type mice after cold challenge. Furthermore, lipid levels in brown adipocytes were higher in Tcrd–/– mice and Vg4–/–Vg6–/– mice than in wild-type mice, suggesting that these knockout mice are defective in lipolysis. Additionally, the induction of thermogenic genes in both BAT and iWAT, and the level of the key thermogenesis regulator mitochondrial brown fat uncoupling protein 1 (UCP1) in BAT, were also lower in Tcrd–/– mice and Vg4–/–Vg6–/– mice than in wild-type mice.

Importantly, these molecular defects had serious physiological consequences — in response to cold challenge, the body temperature of Tcrd–/– mice dropped more rapidly than that of wild-type mice, as the Tcrd–/– mice were unable to increase their energy expenditure. The frequency of γδ T cells in BAT and iWAT of wild-type mice increased substantially 8 h after cold challenge, and γδ T cells were the predominant source of IL-17A production in situ. Furthermore, like Tcrd–/– mice and Vg4–/–Vg6–/– mice, Il17a–/– mice did not upregulate UCP1 in BAT or iWAT, and they had more lipids in brown adipocytes as well as lower expression of thermogenic genes than wild-type mice after cold exposure. Indeed, all Il17a–/– mice had to be rescued from death 5–12 h after cold challenge because of their inability to increase energy expenditure. As the frequency of other cell types important for thermogenic responses was unchanged in BAT and iWAT of Tcrd–/– mice, the thermogenic defects in γδ T cell-deficient animals are likely independent of other immune cell types.

In summary, this study uncovers a new, crucial role for γδ T cells in thermogenic responses in adipose tissues through their production of IL-17A and TNF.