In this issue, Rossaint and colleagues demonstrate that platelets contribute to the resolution of pulmonary inflammation by directly recruiting T regulatory (T reg) cells to the lungs and by transcriptionally reprogramming alveolar macrophages toward an anti-inflammatory phenotype.
In this issue, Le Coz et al. elegantly describe a novel immunodeficiency syndrome caused by mutations in SPI1, affecting blood lineage specification, highlighting the important role of master transcription factors as cellular fate determinants.
Sher and Flynn discuss how sterilizing immunity observed in different TB models could be an opportunity for the identification of novel targets for TB vaccine design.
Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection
This review summarizes and integrates current views on the contribution of inflammatory signals derived from multiple sources to hematopoietic stem cell function and its long-term implications on mutational selection and clonal expansion during aging.
Dysregulation of innate immune- and inflammatory-related pathways is implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. We review the current state of this field and emerging concepts that reveal critical biology and novel therapeutic opportunities.
Inflammation can activate hematopoietic stem and progenitor cells (HSPCs) to proliferate and differentiate, signal the specification of HSPCs during embryonic development, and maintain adult HSPC homeostasis. Collins et al. review the role of inflammatory signaling in these diverse hematopoietic scenarios.
Cells constantly sense their environment to adapt their behavior to changing needs. Kull and Schroeder discuss the requirements, potential, and limitations of current technologies for quantification and manipulation of cellular signaling in the context of inflammatory signaling in hematopoietic cells.
Brief Definitive Reports
The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain
Li et al. develop a new mouse model that recapitulates risperidone-induced metabolic syndrome. Using a combination of transcriptomic, genetic, and electrophysiological approaches, they show that risperidone targets hypothalamic MC4Rs to cause weight gain and that setmelanotide, an MC4R agonist, mitigates its metabolic side effects.
Metabolic bifunctionality of Rv0812 couples folate and peptidoglycan biosynthesis in Mycobacterium tuberculosis
Despite diversification into biochemically distinct enzyme families, rv0812 encodes a single active site that functions as an enzymatically bifunctional aminodeoxychorismate lyase (ADCL) and D–amino acid transaminase (DAAT) and may couple replication and division in Mycobacterium tuberculosis.
Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1
Patients with autoimmune polyendocrine syndrome type-1 (APS-1) have circulating auto-Abs neutralizing most type I interferons. These auto-Abs can underlie life-threatening COVID-19 pneumonia in the general population. The authors report 22 APS-1 patients infected with SARS-CoV-2, including 15 (68%) who developed life-threatening disease.
Genomic analysis of families with unexplained portal hypertension reveals GIMAP5 as a critical regulator of liver sinusoidal endothelial cells and hepatic vascular homeostasis. This study identifies a novel genetic cause of portal hypertension and provides new insight into its pathogenesis.
Technical Advances and Resources
A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies
McCann et al. describe the development and characterization of a new mouse model for studying HIV-specific T cell responses and testing various immunotherapeutic strategies, which they validate by demonstrating enhanced therapeutic effects of autologous HIV-specific T cells augmented with cytokine-loaded nanogels.
CD1a is expressed on Langerhans cells, where it presents lipid antigens to activate T cells. However, skin cells also produce a natural lipid that binds CD1a and blocks T cell response as a mechanism to down-regulate autoreactivity.
Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education
Platelets interact with regulatory T cells and are required for their recruitment into the lung at the onset of inflammation resolution. During this phase, platelets in the lung also orchestrate transcriptomic reprogramming of macrophages toward a reparative phenotype.
PU.1 haploinsufficiency reduces the access of key transcription factors to open chromatin regions, undermines essential stage-specific transcriptional programs, and arrests human B cell development at the pro– to pre–B cell transition.
Peanut-specific CD4+ T cells drive the differentiation of CD209+ DCs, which then act reciprocally on the same CD4+ T cell population to increase Th2 cytokine expression in a positive feedback loop.
TGFβ is essential for the generation of anti-tumor Th9 cells, while it causes resistance against anti-tumor immunity. Pei et al. identify BFAR as an E3 ligase of TGFβR1, through which it coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy.
DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells
Acquired mutations in DNMT3A are common in blood, but their impacts on mature immune cells are poorly understood. Lim et al. demonstrate that DNMT3A defects cause dichotomous DNA methylation defects at enhancers, leading to altered enhancer activity and abnormal gene expression in mature immune cells.
While single-dose COVID-19 vaccines are preferred, two-dose regimens may improve efficacy. Immunogenicity of Ad26.COV2.S is improved in NHPs after a second dose, whereas both regimens protect animals against SARS-CoV-2 disease and elicit neutralizing antibodies against SARS-CoV-2 variants of concern to varying degrees independent of regimen.
Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8+ but not CD4+ T cells
Sasai, Ma, et al. demonstrate that PLCβ4 is specifically required for TCR signaling in CD8+ T cells but not CD4+ T cells, indicating that TCR signaling of CD8+ T cells is qualitatively distinct from that of CD4+ T cells.
LILRB4 strongly suppresses tumor immunity, and LILRB4 blockade alleviates that suppression to provide antitumor efficacy. The authors show that LILRB4 is expressed largely on TAMs and suppresses antitumor immunity. Genetic deletion of LILRB4 or anti-LILRB4 antibody treatment modulates T cells to an effector phenotype and TAMs to a less immunosuppressive phenotype and increases survival against tumor challenge.
T cell anergy is an important peripheral tolerance mechanism to prevent autoimmunity. Nguyen et al. find that T cell anergy develops in the periphery, not in the thymus, and depends upon Cbl-b but not Grail or PD-1.
In a mouse model of chemotherapy-induced peripheral neuropathy, spinal microglia are characterized by the presence of inflammarafts—enlarged, cholesterol-enriched lipid rafts—which organize the inflammatory response. Manipulation of specific mechanisms regulating cholesterol metabolism normalizes inflammarafts and reprograms microglia, resulting in long-lasting alleviation of neuropathic pain.
Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation
Dendritic cells (DCs) are thought to enter afferent lymphatics exclusively through lymphatic capillaries. This study reveals that in inflammation, DCs additionally enter downstream of capillaries into contracting collectors, allowing for a more rapid migration to draining lymph nodes.
Ho et al. demonstrate that old HSCs are extremely resistant to bloodborne systemic rejuvenation approaches and long-term exposure to a young BM niche microenvironment, maintaining a cell-intrinsic aged state. They also show that young HSCs are not affected by old blood or blood-derived factors, an important finding for transplantations in older patients and other emerging anti-aging interventions.
Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus
Using ERVmap, the authors determined that ERV-K102 expression was elevated in SLE patients’ peripheral blood cells and correlated with the interferon signature. IgG antibodies from SLE patients complexed with the K102 envelope protein activate neutrophils and induce NETs.
The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma
Verma et al. present an experimental approach for generation of ILC2 memory for allergic asthma. scRNA-seq and ATAC-seq identify a set of preparedness- and repression-inducing genes with memory formation. Their approach demonstrates a critical role for Fhl2 and ICOS in ILC2 memory.