Interleukin-33 Activates Regulatory T Cells to Suppress Innate γδ T-cell Responses in the Lung
Faustino LD, Griffith JW, Rahimi RA, et al. Nat Immunol. 2020;21:1371–1383.
Endogenous danger signals released upon tissue injury can activate innate immunity, providing a central mechanism by which an organism can respond to damaged self. Such damage-associated molecular patterns (DAMPs) are typically proinflammatory. Consistent with this notion, early studies focused on the airway epithelium-derived DAMP interleukin-33 (IL-33) underscored its role in promoting Th2 effector immunity. Emerging data, however, suggest a broader role for IL-33 in immune regulation and repair.
In the present study, Faustino et al1 used a murine model of pulmonary allergen exposure to examine the role of IL-33 signaling through its receptor ST2, in modulating T regulatory cell (Treg) function during a Th2 immune response. The authors found that ST2+ Treg expand in the lung after allergen exposure in an IL-33 dependent but antigen-independent manner. Interestingly, the development of pulmonary Th2 immunity after allergen exposure was not impaired in the absence of IL-33, suggesting that the antigen-independent regulatory response to airway injury by IL-33-stimulated ST2+ Treg expansion does not alter the adaptive response. The authors went on to show the mechanism by which IL-33-ST2 signaling in Treg regulates local immunity. Specifically, during allergen-induced airway epithelial injury, ST2+ Treg suppress the activation and function of tissue-resident IL-17+ γδ T cells, thereby reducing the production of factors important in eosinophil chemotaxis and mitigating allergen-induced eosinophilic lung inflammation. Taken in the context of existing literature, the authors postulate that their findings suggest dual functions of IL-33: namely, generating a Th2 adaptive response while also activating ST2+ Treg. ST2+ Treg, in turn, produce amphiregulin important for tissue repair and restrain innate IL-17+ γδ T-cell responses to attenuate local inflammation, creating a negative feedback loop to shut off local IL-33 production by injured epithelium.
This study, demonstrating a role for IL-33 induced ST2+ Treg in restricting the early innate immune response and eosinophilic inflammation after airway mucosal injury, is highly relevant to lung transplantation given that the allograft epithelium is constantly subjected to a range of injuries. In addition, the development of intragraft eosinophilic inflammation has been associated with worse outcomes after lung transplantation.2 The findings by Faustino and colleagues raise the possibility that strategies to preserve or enhance IL-33-ST2 signaling could benefit lung transplant recipients. However, the functions of IL-33-ST2 signaling in shaping the alloimmune response or pathobiological processes that influence lung transplant outcomes remain unexplored. Moreover, much of the prior literature in experimental and clinical lung diseases has focused on the proinflammatory effects of IL-33 in driving Th2 immunity. To this end, several biologics that inhibit IL-33-ST2 signaling are in clinical development for asthma or other atopic diseases.
These new data implore clinical and mechanistic studies to understand the influence of IL-33-ST2 signaling in lung transplant recipients, including the impact of IL-33-ST2 signaling on the ability of the allograft to repair and recover from injurious insults such as infection or rejection that increase the risk of chronic graft dysfunction. As the effects of pleiotropic cytokines are generally highly context-dependent, attention should be given to details such as the timing and duration of IL-33 induction. For example, short-lived IL-33 induction may promote repair but failure to shut off IL-33 production may incite a prolonged or aberrant repair process culminating in graft fibrosis. More broadly, the effects of commonly used immunosuppressive strategies on the balance of IL-33-ST2 induced regulatory and adaptive immune responses will need to be established.
In summary, the study by Faustino et al brings to light an important signaling axis that contributes to immune regulation and repair in the lung after airway injury. Understanding the role of IL-33-ST2 Treg in organ transplantation may provide opportunities for exploiting their suppressive mechanisms while preserving healthy graft repair.
Graft IL-33 Regulates Infiltrating Macrophages to Protect Against Chronic Rejection
Li T, Zhang Z, Bartolacci JG, et al. J Clin Invest. 2020;130:5397–5412.
Despite the effective control of acute rejection by conventional immunosuppression, human heart transplant recipients commonly develop a distinct chronic pathology called cardiac allograft vasculopathy (CAV). CAV represents the leading cause of graft loss and death among heart recipients1 and is histologically characterized by progressive intimal thickening followed by the eventual occlusion of cardiac vasculatures including coronary arteries. Both innate and adaptive immune cells have been associated with the progression of CAV lesions. However, to date, therapeutic options for CAV are severely limited, largely due to the lack of a clear mechanistic understanding of its pathogenesis.
In this study,2 Li et al examined the role of local alarmin IL-33 in regulating the function of heart graft infiltrating macrophages to restrict graft inflammation, reduce CAV formation and progression, and ultimately protect against chronic rejection. In a minor mismatched heart transplant model, the authors showed that IL-33 was mainly produced by heart stromal cells shortly after transplantation. This observation was also recapitulated in human heart transplant recipients during diagnosed clinical rejections. Interestingly, the upregulation of local IL-33 appeared to exert an overall antiinflammatory role, as heart allografts with genetic ablation of IL-33 underwent augmented chronic rejection and increased graft infiltration by T cells. Again, this was recapitulated in human heart transplant recipients who suffered from more severe CAV exhibiting decreased intragraft and systemic levels of IL-33. At a cellular level, local IL-33 appeared to function by regulating CCR2+ graft-infiltrating myeloid cells. Specifically, in the absence of IL-33, recipient monocytes infiltrating the heart allograft were more capable of differentiating to proinflammatory Ly6Chi macrophages, which also expressed the molecule inducible nitric oxide synthase (iNOS) to enable their proinflammatory function. These cells, in turn, promoted early allograft vasculopathy, which eventually resulted in vascular occlusion typical of CAV. Encouragingly, using a therapeutic modality consisting of matrix-bound nanovesicles (MBV) embedded with bioreactive IL-33 and adhered to the heart graft via hydrogel immediately following transplantation, the authors were able to rescue the accelerated CAV otherwise seen with IL-33–/– grafts. The authors further demonstrated that the effect of local IL-33 on graft-infiltrating macrophages was mediated through metabolic reprogramming by augmenting their fatty acid uptake and ATP generation via OXPHOS using an intact TCA cycle, resulting in a panel of metabolites most compatible with a regulatory and reparative phenotype of the graft-infiltrating macrophages.
This study by Li et al provides intriguing mechanistic as well as therapeutic insights to CAV. Mechanistically, whether intragraft IL-33 can directly modulate other immune cells that express its receptor ST2, including dendritic cells, CD8, CD4 T cells and Treg, or indirectly through its reprogramming of macrophages, or both, will be important to dissect. This understanding will permit development of IL-33 therapeutics aiming to minimize off-target effects. A pragmatic advantage of macrophage-only targeting is that this phagocytic cell type is more capable of phagocytosing certain drug delivery vehicles, such as nanobiologics. Therefore, macrophages are more susceptible to drug effects. Another clinically relevant question is the potential efficacy of “delayed” IL-33 therapy in the prevention of CAV development. If proven efficacious, this therapeutic modality can be used in already transplanted patients as a CAV prophylactic treatment. This approach would require an understanding of the timing of the metabolic switch from an inflammatory to reparative macrophage phenotype in the graft during the posttransplant course, permitting precise determination of the optimal timing for this therapeutic modality to be effective.
In summary, the current study identifies IL-33 as a mechanistic link between tissue injury, macrophage reprogramming, and the development of CAV. It provides a novel therapeutic target for prophylaxis and treatment of CAV.
1. Faustino LD, Griffith JW, Rahimi RA, et al. Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung. Nat Immunol. 2020;21:1371–1383.
2. Verleden SE, Ruttens D, Vandermeulen E, et al. Elevated bronchoalveolar lavage eosinophilia correlates with poor outcome after lung transplantation. Transplantation. 2014;97:83–89.
1. Loupy A, Coutance G, Bonnet G, et al. Identification and characterization of trajectories of cardiac allograft vasculopathy after heart transplantation: a population-based study. Circulation. 2020;141:1954–1967.
2. Li T, Zhang Z, Bartolacci JG, et al. Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection. J Clin Invest. 2020;130:5397–5412.