Interleukin (IL)-33 is a recently characterized IL-1 family member that is proposed to function as an alarmin, or endogenous signal of cellular damage, as well act as a pleiotropic cytokine. The ability of IL-33 to potentiate both Th1 and Th2 immunity supports its role in pathogen clearance and disease immunopathology. Yet, IL-33 restrains experimental colitis and transplant rejection by expanding regulatory T cells (Treg) via an undefined mechanism. We sought to determine the influence of IL-33 on hematopoietic cells that drives Treg expansion and underlies the therapeutic benefit of IL-33 administration. Herein, we identify a feedback loop where conventional mouse CD11c+ dendritic cells (DC) stimulated by IL-33 secrete IL-2 to selectively expand IL-33R(ST2+) suppressive CD4+Foxp3+ Treg. Interestingly, this occurs in the absence of classical DC maturation, and DC-derived (innate) IL-2 increases ST2 expression on both DC and interacting Treg. ST2+ Treg represent an activated subset of Foxp3+ cells, demonstrated to be ICOShiCD44hi compared to their ST2− counterparts. Furthermore, while studies have shown that IL-33-exposed DC promote Th2 responses, we reveal that ST2+ DC are required for IL-33-mediated in vitro and in vivo Treg expansion. Thus, we have uncovered a relationship between IL-33 and innate IL-2 that promotes the selective expansion of ST2+ Treg over non-Treg. These findings identify a novel regulatory pathway driven by IL-33 in immune cells that may be harnessed for therapeutic benefit or for robust expansion of Treg in vitro and in vivo.

Key Points Peri-alloHCT IL-33 delivery prevents acute GVHD through MAPK-dependent expansion of radiation-resistant recipient ST2+ Tregs. IL-33–expanded Tregs regulate myeloid cell differentiation and activation, and limit effector T-cell accumulation in GVHD-target tissue.

Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes.

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temic expansion of ST2 + Tregs (29,30). IL-33 expressed by fibrogenic/adipogenic progenitors in skeletal muscle has also been shown to regulate skeletal muscle Treg homeostasis and support muscle regeneration (31). Related studies have suggested a direct, cardioprotective role for rIL-33 against hypertrophy resulting from cardiac overload (32) and fibrosis after myocardial infarction (33). However, delivery of rIL-33 also aggravates autoimmune eosinophilic pericarditis during coxsackievirus B3 infection (34), suggesting that IL-33 can contribute to cardiac inflammation. IL-33 expression has been reported in cardiac fibroblasts (32) and the vasculature ( 35), yet how the expression of this alarmin is modulated in cardiac allografts or impacts outcomes was unknown.Using IL-33-deficient heart grafts in a mouse chronic rejection model we have established that IL-33 stands out among identified alarmins and limits differentiation of proinflammatory macrophages to prevent chronic rejection. Specifically, transplants lacking IL-33 displayed dramatically accelerated chronic rejectionassociated vasculopathy and subsequent fibrosis orchestrated by graft-infiltrating recipient proinflammatory macrophages. IL-33expressing heart grafts in recipients with ST2-deficient macrophages also displayed increased graft infiltration by proinflammatory macrophages and accelerated graft loss. Mechanistic studies demonstrated that IL-33 promoted a reparative macrophage phenotype through a metabolic reprograming involving augmented oxidative phosphorylation (OXPHOS) and fatty acid (FA) uptake. We also revealed that IL-33 prevents proinflammatory stimuli-induced disruption of the tricarboxylic acid (TCA) cycle that shifts macrophage metabolism to anaerobic glycolysis and generates proinflammatory metabolites (36,37). Restoration of IL-33 to IL-33-deficient heart transplants using vesicles in ECM-derived hydrogel immediately after transplantation profoundly reduced the frequency of proinflammatory myeloid cells in the graft and prevented graft loss to chronic rejection. Thus, the local delivery of IL-33 in ECM-based materials after transplantation may be a practical and promising biologic for chronic rejection prophylaxis.