Type 2 immunity is critical for defense against cutaneous infections, but also underlies the development of allergic skin diseases. We report the identification in normal murine dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depends on interleukin 7 (IL-7) and constitutively produces IL-13. Intravital multiphoton microscopy revealed that dermal ILC2 specifically interact with mast cells, whose function was suppressed by IL-13. Treatment of Rag1−/− mice with IL-2 resulted in the expansion of activated, IL-5-producing dermal ILC2, leading to spontaneous dermatitis characterized by eosinophil infiltrate and activated mast cells. Our data show that ILC2 exhibit both pro- and anti-inflammatory properties and uncover a novel interactive pathway between two innate immune cell populations implicated in type 2 immunity and allergic diseases.

Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.

Summary How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5A H ) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.

SUMMARY T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial FAO, before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation – cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity essential for future T cell responses.

Defining the immune mechanisms underlying protective immunity to helminth infection remains an important challenge. Here we report that lung CD4 þ T cells and Group 2 innate lymphoid cells (ILC2s) work in concert to block Nippostrongylus brasiliensis (Nb) development in the parenchyma within 48 h in mice. Immune-damaged larvae have a striking morphological defect that is dependent on the expansion of IL-13-producing ILC2 and CD4 þ T cells, and the activation of M2 macrophages. This T-cell requirement can be bypassed by administration of IL-2 or IL-33, resulting in expansion of IL-13-producing ILC2s and larval killing. Depletion of ILC2s inhibits larval killing in IL-2-treated mice. Our results broaden understanding of ILC2's role in immunity to helminths by demonstrating that they not only act as alarmin sensors, but can also be sustained by CD4 þ T cells, ensuring both the prompt activation and the maintenance of IL-13-dependent M2 macrophage immunity in the lung.

Highlights d FABP5 inhibition in Tregs alters mitochondria and enhances suppression d Disrupting FABP5 in Tregs results in mtDNA release and type I IFN signaling d cGAS/-STING-dependent type I IFN signals promote Treg IL-10 production d Tumor Tregs exhibit mitochondrial alterations and a type I IFN gene signature

The H2.0-like homeobox transcription factor (HLX) regulates hematopoietic differentiation and is overexpressed in Acute Myeloid Leukemia (AML), but the mechanisms underlying these functions remain unclear. We demonstrate here that HLX overexpression leads to a myeloid differentiation block both in zebrafish and human hematopoietic stem and progenitor cells (HSPCs). We show that HLX overexpression leads to downregulation of genes encoding electron transport chain (ETC) components and upregulation of PPARδ gene expression in zebrafish and human HSPCs. HLX overexpression also results in AMPK activation. Pharmacological modulation of PPARδ signaling relieves the HLX-induced myeloid differentiation block and rescues HSPC loss upon HLX knockdown but it has no effect on AML cell lines. In contrast, AMPK inhibition results in reduced viability of AML cell lines, but minimally affects myeloid progenitors. This newly described role of HLX in regulating the metabolic state of hematopoietic cells may have important therapeutic implications.

Highlights d Acetate restores IFN-g in TILs and T cells under prolonged glucose-restriction d Acetate promotes histone acetylation and chromatin accessibility in T cells d ACSS expression contributes to optimal effector T cell function during cancer