γδ T cells are critical contributors to tissue homeostasis. Recent research identifies an unexpected role for γδ T cell–derived IL-17F in promoting sympathetic innervation and tissue thermogenesis through the induction of the cytokine TGF-β in adipose cells.
IL-17A- and IL-17F-producing γδ T cells (Tγδ17 cells) are tissue-resident cells critical in both tissue defense and homeostasis. As innate-like cells, Tγδ17 cells undergo effector ‘preprogramming’ in the fetal thymus during ontogeny, which allows them to mount rapid responses following exposure to inflammatory cytokine stimulation1. Newly developed Tγδ17 cells egress from the thymus and seed discrete barrier and non-lymphoid tissues, such as the dermis, lungs and female reproductive tract, where they establish long-lived tissue residency. In Nature, Hu et al. have identified an unexpected function for Tγδ17 cells in promoting sympathetic innervation by driving the expression of neurotrophic TGF-β1 in adipose cells through an IL-17F–IL-17 receptor C (IL–17RC) signaling axis2.
The sympathetic nervous system innervates tissues in nearly every organ to maintain homeostasis and regulate physiological processes such as blood circulation, body temperature and energy expenditure3. Adaptive thermogenesis is the process of heat production in brown adipose tissue (BAT), in which secretion of norepinephrine by sympathetic nerves activates lipolysis and thermogenic respiration in adipocytes and leads to the release of energy as heat (Fig. 1). Reciprocally, peripheral organs produce neurotrophic factors that promote sympathetic innervation4, but the details of this crosstalk in BAT are unclear. Previous work has identified an adipocyte-specific pathway that affects sympathetic axon growth and involves the endoplasmic reticulum protein CLSTN3β and the secreted neurotrophic factor S100B5. An additional, unanticipated axis for the regulation of adipose thermogenesis was found to be mediated by immune cells that reside in or infiltrate the BAT, including macrophages, eosinophils, group 2 innate lymphoid cells and T cells6. In the current study, Hu et al. investigated the molecular basis of this complex communication between immune, tissue and nervous system cells.
To pinpoint the lymphoid cell types and the signaling mediators that influence adaptive thermogenesis, in an unbiased approach, Hu et al. subjected several mutant strains of mice to a cold-tolerance test. Mice with deficiencies in Rag2 or Tcrd, but not mice that selectively lack B cells or αβ T cells, showed substantial defects in maintaining body temperature, identifying the γδ T cells as key promoters of adaptive thermogenesis. Within BAT, the innate-like Vγ6+ Tγδ17 cell subset makes up a substantial fraction of the γδ T cell population2. While IL-17A production by Vγ6+ Tγδ17 cells was previously implicated in the regulation of thermogenesis7, Hu et al. found that IL-17F, rather than IL-17A, had a significant impact on cold tolerance, revealing a distinct mechanism for the crosstalk between Tγδ17 cells and adipocytes. There are two IL-17 receptors in mice, IL-17RA and IL-17RC, the latter of which binds only IL-17F. Adipocyte-specific deletion of Il17rc in mice (Ad-IL-17RC cKO mice hereafter), but not Il17ra deficiency, phenocopied the impaired cold tolerance of Il17f–/– mice, suggesting that IL-17RC was the physiological receptor for IL-17F in promoting thermogenesis. Defects in adaptive thermogenesis are associated with susceptibility to diet-induced obesity and metabolic dysfunction. Accordingly, Ad-IL-17RC cKO mice fed a high-fat diet gained weight more rapidly and displayed impaired glucose tolerance, increased lipid accumulation in BAT and enlarged white adipose tissue deposits, as compared to wild-type littermates. γδ T cell–deficient mice also displayed metabolic phenotypes consistent with BAT dysfunction. Together, these findings support a model in which Tγδ17 cells promote thermogenesis by signaling to adipocytes via an IL-17F–IL-17RC axis (Fig. 1).
In pursuing the underlying cause of impaired thermogenesis in Ad-IL-17RC cKO mice, Hu et al. found that IL-17RC-derived signals promote adipose innervation. Ad-IL-17RC cKO mice, or those that lacked γδ T cells or IL-17F expression, had significantly fewer BAT sympathetic neurons than wild-type littermates. Conversely, mice transgenic for a Vγ6+Vδ1+ TCR, in which this γδ T cell subset is overrepresented, had enhanced innervation of BAT, indicating the involvement of Tγδ17 cells in the growth of sympathetic neurons. Notably, overcoming the BAT nerve deficit in Ad-IL-17RC cKO mice through the overexpression of the neurotrophic pathway factors S100B or CLSTN3β in BAT was sufficient to restore the cold intolerance and lipid accumulation in these mice, indicating that the thermogenic defect was related to impaired adipose innervation. Loss of IL-17RC also dampened thermal responses in BAT following experimental activation of upstream sympathetic premotor neurons, revealing that the IL-17F–IL-17RC axis in γδ T cells and adipocytes additionally promotes sympathetic nerve function. This pathway also influenced other target tissues of sympathetic innervation, such as salivary glands and lungs, implying a more general neurotrophic function of Tγδ17 cells through the activity of IL-17RC.
To determine the mechanistic link between the IL-17F–IL-17RC pathway and nerve growth, Hu et al. used transcriptional and proteomic approaches to reveal that the TGF-β signaling pathway was altered in the IL-17RC-deficient BAT. Notably, expression of TGF-β1 was downregulated in adipocytes from Ad-IL-17RC cKO mice and also in the salivary glands and the lungs of Il17rc–/–, Il17f–/– and Tcrd–/– mice, implicating Tγδ17 cell–derived IL-17F as a driver of TGF-β1. TGF-β1 is a compelling target of IL-17RC signaling; prior work implicates TGF-β signals in promoting neuronal development, survival, and regeneration and in the expression of neurotrophic factors in the central nervous system8, whereas its effects on the peripheral nervous system are less defined. Now, Hu et al. identify TGF-β1 as the molecular link connecting IL-17F–IL-17RC signaling with neurotrophic support of BAT sympathetic neurons. Indeed, experimental restoration of TGF-β1 expression was sufficient to alleviate the defect in BAT sympathetic innervation and thermogenesis in Ad-IL-17RC cKO mice, and, conversely, blocking TGF-β signaling with a neutralizing antibody or small molecule inhibitor sensitized wild-type mice to cold exposure.
In future work, it will be important to uncover the mechanism by which TGF-β1 influences nerve growth, which will involve identifying the precise cellular target of TGF-β1 in BAT and whether it acts directly on sympathetic nerves, or indirectly by regulating the availability of other neurotrophic factors or by remodeling the extracellular matrix8. Of note, TGF-β1 also promotes the expression of IL-17A in γδ T cells and the development of Tγδ17 cells9, raising the possibility that adipocyte-derived TGF-β may additionally contribute to the cytokine production or stability of BAT-resident Tγδ17 cells, thus supporting a positive feedback loop that would sustain prothermogenic levels of IL-17F and TGF-β1. Because previous work has implicated IL-17A in promoting adipose thermogenesis7, further understanding of the distinct contributions of the two IL-17 isoforms will help contextualize the role of Tγδ17 cell factors in this process. Beyond mouse models, it will be beneficial to establish whether the IL-17F–IL-17RC–TGF-β1 axis connecting Tγδ17 cells, adipocytes and sympathetic neurons is conserved in human BAT. Indeed, thermogenic fat has garnered much attention as a potential therapeutic target for addressing metabolic diseases due to its capacity to increase energy expenditure and protect against obesity in rodent models10. Capitalizing on the novel molecular circuitries defined in this study may provide new clinical interventions for driving thermogenic fat activity and combatting the growing obesity crisis.
To date, the function of Tγδ17 cells was thought to be largely restricted to defense against infection and pathogenic autoimmune responses11. However, over the last few years, it has become increasingly appreciated that Tγδ17 cells play central roles in the maintenance of steady-state tissue physiology and repair following injury. Recent work has highlighted the function of Tγδ17 cell populations in regulating adipose tissue immune cell homeostasis7, bone regeneration12, and synaptic plasticity and short-term memory formation in the brain13. The work of Hu et al. adds to the list of emerging tissues and homeostatic processes that depend on tissue-resident Tγδ17 cells and provides further functional links between the immune and nervous systems.
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Ciofani, M. Tγδ17 cells build up the nerve. Nat Immunol 21, 367–368 (2020). https://doi.org/10.1038/s41590-020-0642-4