Mucosal barriers are composed of an organized network of tightly joined cells that act as a critical first line of defense against pathogens. With their tissue homing properties and ability to sense environmental signals, gamma delta (γδ) T cells play a key role in this process. In particular, they contribute to immune surveillance and protect the host against infection through the production of IL-17A. For instance, they have been shown to promote clearance of the bacteria Streptococcus pneumoniae and Mycobacterium tuberculosis—among others—by recruiting neutrophils to the lung (reviewed in1,2). However, IL-17A-producing γδ T cells (γδ17 T cells) can also elicit damage after infiltrating or accumulating in target tissues, thus promoting inflammatory pathology.1 Therefore, γδ17 T cells represent a double-edged sword, and their homeostasis needs to be tightly controlled to preserve tissue structure and physiological functions. A recent study by Faustino et al.3 uncovered a crucial role for ST2+ regulatory T cells (Tregs) as modulators of the early innate γδ17 T cell response to mucosal injury in the lung. By highlighting the effects of the alarmin IL-33 on this process, this must read paper adds a new dimension to our understanding of how the immune system prevents collateral tissue damage while responding to allergens.
Pulmonary inflammation can be generated experimentally with a standard mouse model of allergic asthma induced by the inhalation of house dust mites (HDM). After a single exposure to the aeroallergen as a sensitization step, mice are challenged daily by intranasal administration of HDM. This protocol leads to severe lung injury and induces a type 2 immune response marked by eosinophilia and lymphocytosis in the parenchyma and airways, as well as increased mucus production. In addition to massive type 2 cell infiltration in the lung, Faustino et al. identified a substantial population of Treg cells that express the receptor for IL-33 (also called ST2). Importantly, these ST2+ Treg cells accumulated very early in the time course of the pathology, i.e., before their adaptive immune cell partners. Of note, the authors observed the same ST2+ Treg cell accumulation in the airways of allergic human volunteers after aeroallergen exposure, highlighting the translational relevance of their study.
Interestingly, the authors further showed that this accumulation of ST2+ Treg cells in the lung is unlikely to be driven by activation of the T cell receptor (TCR). Indeed, the authors failed to detect any HDM-specific ST2+ Treg cells, in contrast to conventional Th2 and ST2− Treg populations, by fluorescent tetramer assay. Rather, they observed reduced activation and proportions of ST2+ Treg cells in the HDM-exposed lungs of mice deficient in IL-33, demonstrating that Treg cells can directly respond to this alarmin.
However, IL-33 can exert varying effects on immune cells, and whether this alarmin can directly impact Treg cells remains elusive. In this study, for the first time, Faustino et al. elegantly addressed this issue by generating a new conditional KO mouse model in which ST2 is specifically deleted in the Treg compartment. Surprisingly, the authors collected the same numbers of Treg cells from the lungs of these genetically modified mice as from the lungs of their control littermates at steady state and upon inflammation. Consistent with another recent study,4 these data support the existence of cell-extrinsic IL-33-mediated control of ST2+ Treg cell homeostasis in the tissue, but the cellular and molecular mechanistic details still need to be investigated.
Importantly, mice harboring ST2-deficient Treg cells displayed an increased number of eosinophils and neutrophils in the lung parenchyma, as well as a substantial accumulation of γδ T cells but not other innate or adaptive immune cells in the airways. These γδ T cells were particularly enriched in activated cells and biased towards the production of IL-17A. By analyzing mice lacking γδ T cells or by injecting an anti-IL17A blocking antibody, the authors demonstrated that IL-17A-producing γδ T cells stimulate the production of the eosinophil-attracting chemokines CCL11 and CCL24. Thus, these findings establish a detrimental role of γδ17 T cells as innate drivers of allergic inflammation in the lung and highlight the specific inhibition of γδ T cells by ST2+ Treg cells upon IL-33 stimulation. To unravel the mechanisms underlying this targeted immunosuppression, the authors first performed a microscopic analysis that documented Treg-γδ T cell interactions within the airways of HDM-treated mice. Transcriptomic analysis further revealed that pulmonary ST2+ Treg cells exhibit specific expression of Ebi3 and Il12a, two genes encoding the subunits of the inhibitory cytokine IL-35. Importantly, the authors demonstrated that IL-33 was indispensable for the production of IL-35 by ST2+ Treg cells in vitro. Finally, they induced HDM-allergic inflammation in mice bearing Treg cells unable to produce IL-35 or mice concomitantly treated with an anti-IL35 neutralizing antibody. In both cases, they observed a substantial accumulation of γδ17 T cells in the lung parenchyma and severe eosinophilia, similar to those observed in HDM-treated mice bearing Treg cells unable to sense IL-33.
Altogether, these findings provide exciting insights into how regulatory mechanisms can modulate the immune response to minimize tissue damage without impacting antimicrobial activity.
We believe that the study is highly relevant at different levels. First, it complements a recent article showing that γδ17 T cells enhance the production of epithelial IL-33 in the lung, which promotes Treg cell expansion and amphiregulin production upon influenza virus infection in neonates.5 Interestingly, this mechanism seems to be conserved in steady-state adipose tissue,6 highlighting a potential evolutionary link between these tissue-resident immune subsets. Collectively, these data underlie a complex feedback loop that ensures the maintenance of Treg cells to support tissue homeostasis and promote tissue repair upon injury (Fig. 1).
From a more fundamental standpoint and consistent with previous studies uncovering a role for Tregs in tissue repair,5 Faustino et al. point to an intriguing innate-like mode of response triggered by inflammatory mediators released from the tissue environment rather than conventionally activated through the TCR. This may guarantee action during an optimal time window that would allow Tregs to rapidly counteract potential pathogenic innate inflammatory responses during infectious lung injury, such as that mediated by γδ17 T cells. Again, this mechanism may extend to a myriad of other contexts and organs, as recently demonstrated in neuroinflammation, with ST2+ Treg cells restricting the accumulation of γδ17 T cells at Experimental Autoimmune Encephalomyelitis (EAE) onset.4
In addition to reporting their detrimental role in (neuro)inflammation, recent studies have revealed unexpected novel functions for γδ17 T cells in supporting steady-state physiology to maintain tissue homeostasis.2 However, the role of pulmonary γδ T cells in this context remains unclear, and exploring their interactions with Treg cells may reveal interesting clues and new physiological roles, far beyond defending the host against environmental insults. The perinatal period may be particularly interesting, with critical modifications of the tissue architecture that induce the activation of the IL-33 pathway upon inhalation of potential allergens, thus enhancing type 2 immunity and the risk of asthma development in early life.7 Interestingly, this phase of postnatal lung alveolarization also includes the colonization of the airway microbiota, which seems to shape the effector programs of different resident immune populations, namely, the Treg compartment.8
In line with this, Faustino et al. posed important open questions for future investigations, namely, regarding the influence of the microbiota on Treg-γδ17 T cell crosstalk in the lung. Of note, intestinal dysbiosis has previously been shown to improve the outcome of brain ischemic injury by promoting the suppressive activity of Tregs, which limits the migration of pathogenic γδ T cells from the gut to the meninges.9 More recent data also revealed a detrimental impact of the commensal microbiota on cancer progression through promotion of γδ17 T cell proliferation in a model of lung adenocarcinoma.10 With both Treg and γδ17 T cells commonly associated with poor prognosis in cancer, this new intriguing interplay between these two subsets may hold promise for the design of new immunotherapies against tumors.
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Darrigues, J., Ribot, J.C. γδ T cells, Tregs and epithelial cells interact with IL-33 in the lung. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-020-00631-2