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Blacher et al. examine the effect of aging on the myeloid circadian clock. They find that aging disrupts circadian transcriptional responses and identify KLF4 as a critical oscillating transcription factor that regulates macrophage gene expression and phagocytosis.
Wang et al. show that the Rictor-dependent mTORC2–Akt pathway is needed to maintain CD4+ memory cells. This axis acts, in part, by suppressing mitoROS generation and subsequent oxidation of membrane phospholipids, which then triggers cell death by ferroptosis.
Kubo et al. report two kindreds that exhibit a deficiency of iRHOM2, which interacts with ADAM17, leading to defective release of TNF and CD62L and resulting in altered immune responses to opportunistic infections.
SARS-CoV-2 infection is milder in children, but direct comparison with adults is rare. Here the authors show that immune responses are higher in children, retained for 12 months or longer and can neutralize Alpha, Beta and Delta variants.
Shukla, Samaniego-Castruita and colleagues show that loss of TET methylcytosine dioxygenases in B cells is associated with increased DNA–RNA hybrids and G-quadruplex DNA structures in parallel with genomic instability and development of germinal center-derived lymphomas.
Ghosh et al. report findings showing that the atypical kinase RIOK2 functions as a winged helix-turn-helix domain containing transcription factor that regulates the differentiation of human hematopoietic stem and progenitor cells toward erythroid, myeloid and megakaryocytic lineages. RIOK2 enhances GATA1 and KLF1 expression, while suppressing other transcription factors like RUNX3, SPI1 and GATA2.
Peng et al. find that immunodominant cytotoxic T lymphocytes (CTLs) specific for NP105–113-B*07:02 are associated with reduced COVID-19 severity. Mechanistically, NP105–113-B*07:02-specific CTLs show potent antiviral functionality and may represent rational T cell vaccine targets.
Chronic viral infection leads to a dysregulation of germinal center B cell responses. Di Pietro et al. show that the epigenetic modifier BMI-1 promotes this dysfunctional response and that targeting BMI-1 in B cells can restore humoral immunity and accelerate viral clearance.
Mitochondrial aspartate regulates ER morphology and co-translational translocation via BiP ADP ribosylation. In T cells from patients with rheumatoid arthritis, mitochondrial aspartate is deficient, resulting in ER expansion and excessive production of the pro-inflammatory cytokine TNF.
Alter and colleagues show that IgM titers in the plasma and bronchoalveolar lavage fluid represent markers of reduced Mtb burden in rhesus macaques vaccinated intravenously with Bacille Calmette–Guérin.
Mutations in the RNA-binding proteins Roquin-1 or Regnase-1 cause systemic autoimmunity. Heissmeyer and colleagues show that Roquin-1 and Regnase-1 physically interact and thereby regulate CD4+ and CD8+ T cell metabolism and functionality.
Snell et al. examine the heterogeneity of CD4+ T cells in chronic viral infection, showing that PD-L1 blockade enhances a cytotoxic gene program in antigen-specific TH1 cells and can restore antiviral CD4+ T cell killer function.
Ronchese and colleagues show that IL-13 secreted homeostatically by dermal ILCs contributes to the differentiation of a CD11blo type 2 dendritic cell subset, which supports the development of TH2 cells and curtails the development of TH17 cells in the skin of mice and humans.
During homeostasis TH1 cells activate a cell-intrinsic inflammatory shutdown program and shift to IL-10 production. Chauss et al. find that this TH1 homeostatic program is dependent on vitamin D signaling and is disrupted in severe COVID-19.
Krebs and colleagues identify multiple mAbs that recognize either the RBD or the NTD of SARS-CoV-2 spike protein that have potent cross-neutralizing activities against variants of concern. Combinatorial mAb cocktails have complementary effects on viral neutralization and Fc effector functions and can protect against SARS-CoV-2 escape mutants.
Tumor-associated macrophages support an immunosuppressive tumor microenvironment. Di Conza et al. uncover how IRE1–XBP1 and IRE1−STAT3 endoplasmic reticulum stress responses pathways are engaged by tumor-derived lipids to orchestrate pro-tumorigenic features and survival in tumor-associated macrophages.
Epithelial cells can use an immune-like mechanism to extrude neighboring precancerous cells; however, the recognition and control mechanisms of this process are unclear. Maruyama and colleagues demonstrate that LILRB3 on normal epithelial cells recognizes elevated MHC class I on transformed cells and triggers the extrusion process.
Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic diseases such as graft-versus-host and inflammatory bowel disease. Here the authors identify a critical role for the alteration of the IEC-specific mitochondrial complex II component succinate dehydrogenase A in the regulation of the severity of T cell-mediated intestinal diseases.
The antiviral factor ISG15 can be conjugated to other proteins through ISGylation. Sanyal and colleagues find that viruses can modulate ISGylation, which in turn alters macrophage responses and can result in exaggerated inflammation in COVID-19.
Transgenerational transmission of acquired immunological traits has been demonstrated in invertebrates and plants but not mammals. Katzmarski et al. demonstrate that trained immunity that protects against heterologous infections can be transmitted to F2 offspring.