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Issues

Brief Definitive Report

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.

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.

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.

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.

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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Technical Advances and Resources

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.

Insights

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.

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