Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6–73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients’ autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10−5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10−5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10−10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.

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Correction: Profiling HPV-16–specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients

Bhatt, Kunal H.;Neller, Michelle A.;Srihari, Sriganesh;Crooks, Pauline;Lekieffre, Lea;Aftab, Blake T.;Liu, Howard;Smith, Corey;Kenny, Liz;Porceddu, Sandro;Khanna, Rajiv

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.2020038910192022cpmid: 36282237

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Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses

Chaudhary, Vidyanath;Ah Kioon, Marie Dominique;Hwang, Sung-Min;Mishra, Bikash;Lakin, Kimberly;Kirou, Kyriakos A.;Zhang-Sun, Jeffrey;Wiseman, R. Luke;Spiera, Robert F.;Crow, Mary K.;Gordon, Jessica K.;Cubillos-Ruiz, Juan R.;Barrat, Franck J.

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.20221085pmid: 36053251

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Metabolic features of innate lymphoid cells

Yu, Huiyang;Jacquelot, Nicolas;Belz, Gabrielle T.

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.20221140pmid: 36301303

Innate and adaptive immune cells are found in distinct tissue niches where they orchestrate immune responses. This requires intrinsic and temporal metabolic adaptability to coordinately activate the immune response cascade. Dysregulation of this program is a key feature of immunosuppression. Direct or indirect metabolic immune cell reprogramming may offer new approaches to modulate immune cells behavior for therapy to overcome dysregulation. In this review, we explored how metabolism regulates lymphocytes beyond the classical T cell subsets. We focus on the innate lymphoid cell (ILC) family, highlighting the distinct metabolic characteristics of these cells, the impact of environmental factors, and the receptors that could alter immune cell functions through manipulation of metabolic pathways to potentially prevent or treat various diseases.

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A glycan-based approach to cell characterization and isolation: Hematopoiesis as a paradigm

Piszczatowski, Richard T.;Schwenger, Emily;Sundaravel, Sriram;Stein, Catarina M.;Liu, Yang;Stanley, Pamela;Verma, Amit;Zheng, Deyou;Seidel, Ronald D.;Almo, Steven C.;Townley, Robert A.;Bülow, Hannes E.;Steidl, Ulrich

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.20212552pmid: 36066492

Cell surfaces display a wide array of molecules that confer identity. While flow cytometry and cluster of differentiation (CD) markers have revolutionized cell characterization and purification, functionally heterogeneous cellular subtypes remain unresolvable by the CD marker system alone. Using hematopoietic lineages as a paradigm, we leverage the extraordinary molecular diversity of heparan sulfate (HS) glycans to establish cellular “glycotypes” by utilizing a panel of anti-HS single-chain variable fragment antibodies (scFvs). Prospective sorting with anti-HS scFvs identifies functionally distinct glycotypes within heterogeneous pools of mouse and human hematopoietic progenitor cells and enables further stratification of immunophenotypically pure megakaryocyte–erythrocyte progenitors. This stratification correlates with expression of a heptad of HS-related genes that is reflective of the HS epitope recognized by specific anti-HS scFvs. While we show that HS glycotyping provides an orthogonal set of tools for resolution of hematopoietic lineages, we anticipate broad utility of this approach in defining and isolating novel, viable cell types across diverse tissues and species.

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EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors

Lenaerts, Aurelie;Kucinski, Iwo;Deboutte, Ward;Derecka, Marta;Cauchy, Pierre;Manke, Thomas;Göttgens, Berthold;Grosschedl, Rudolf

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.20212437pmid: 36048017

Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low-level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit an augmented myeloid differentiation potential and a transcriptome with an enriched C/EBPα signature. Correspondingly, EBF1 binds the Cebpa enhancer, and the deficiency and overexpression of Ebf1 in MPP3 and MPP4 cells lead to an up- and downregulation of Cebpa expression, respectively. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate.

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Expression of Concern: In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.2012095009272022epmid: 36191251

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Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine

Okoye-Okafor, Ujunwa Cynthia;Javarappa, Komal K.;Tsallos, Dimitrios;Saad, Joseph;Yang, Daozheng;Zhang, Chi;Benard, Lumie;Thiruthuvanathan, Victor J.;Cole, Sally;Ruiz, Stephen;Tatiparthy, Madhuri;Choudhary, Gaurav;DeFronzo, Stefanie;Bartholdy, Boris A.;Pallaud, Celine;Ramos, Pedro Marques;Shastri, Aditi;Verma, Amit;Heckman, Caroline A.;

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Innatus immunis: Evolving paradigm of adaptive NK cells

Khalil, Mohamed;Malarkannan, Subramaniam

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.20221254pmid: 36066493

The mechanisms that govern the development of adaptive-like NK cells are elusive. Shemesh et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220551) report that the development of FcRγ−/low adaptive-like NK cells requires reduced mTOR activity and depends on TGF-β or IFN-α. These findings provide exciting new molecular blueprints explaining the development and functions of adaptive-like NK cells.

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Broader Epstein–Barr virus–specific T cell receptor repertoire in patients with multiple sclerosis

Schneider-Hohendorf, Tilman;Gerdes, Lisa Ann;Pignolet, Béatrice;Gittelman, Rachel;Ostkamp, Patrick;Rubelt, Florian;Raposo, Catarina;Tackenberg, Björn;Riepenhausen, Marianne;Janoschka, Claudia;Wünsch, Christian;Bucciarelli, Florence;Flierl-Hecht, Andrea;Beltrán, Eduardo;Kümpfel, Tania;Anslinger, Katja;Gross, Catharina C.;Chapman, Heidi;

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Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I–stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1–controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1–PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.

Will, Britta

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.20212228pmid: 36053753

Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant–ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.

Kaplan, Ian;

Brassat, David;

Wekerle, Hartmut;

Kerschensteiner, Martin;

2022 The Journal of Experimental Medicine

doi: 10.1084/jem.20220650pmid: 36048016

Epstein–Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen–specific TCRβ sequences. We detected more MHC-I–restricted EBV-specific TCRβ sequences in MS patients. Differences in genetics or upbringing could be excluded by validation in monozygotic twin pairs discordant for MS. Anti–VLA-4 treatment amplified this observation, while interferon β– or anti-CD20 treatment did not modulate EBV-specific T cell occurrence. In healthy individuals, EBV-specific CD8+ T cells were of an effector-memory phenotype in peripheral blood and cerebrospinal fluid. In MS patients, cerebrospinal fluid also contained EBV-specific central-memory CD8+ T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS.