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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.
Weisel and colleagues provide a resource that phenotypically profiles naive and memory B cells and provides a comparative analysis of memory B cells found in humans versus mice.
The immunological processes occurring in the upper respiratory tract during COVID-19 are relatively poorly understood. Jochems and colleagues observe durable changes in the upper respiratory tract following SARS-CoV-2 infection, including evidence of virus-specific tissue memory T cells.
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.
Zhong et al. utilize B6/Cast F1 hybrid mice to examine transcriptional regulation of T cell gene expression upon activation induced by viral challenge. They describe gene accessibility changes that lead to differential gene expression and report a hierarchy of transcription factor families that mediate the chromatin dynamics.
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.
Lanz and colleagues show that the first dose of the BNT162b2 mRNA vaccine against SARS-CoV-2 activates a non-neutralizing recall response predominantly targeting the S2 subunit of the spike protein, while the second dose boosts neutralizing antibodies specific for the receptor binding domain of the spike protein.
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.
Haas, Velten and colleagues use single-cell multiomics of human blood and bone marrow to generate a reference map allowing the quantitative linking of cytometry and proteo-genomic information.
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.
Jiang and colleagues describe a high-dimensional, high-throughput tetramer-associated TCR sequencing (TetTCR-SeqHD) method to simultaneously profile TCR sequences, cognate antigen specificities, targeted gene expression and surface-protein expression from tens of thousands of single cells.
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.