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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.
Mitochondria regulate endoplasmic reticulum (ER) size and protein maturation in healthy cells by releasing aspartate, regenerating cytoplasmic NAD+ and ADP-ribosylating the ER stress sensor BiP. In the autoimmune disease rheumatoid arthritis, a deficiency in mitochondrial aspartate in T cells causes an increase in ER size and excess production of the inflammatory mediator tumor necrosis factor (TNF), driving tissue inflammation.
In patients with rheumatoid arthritis, a short supply of aspartate in the mitochondria can force the endoplasmic reticulum of T cells to generate transmembrane TNF, which in turn contributes to synovial inflammation.
Analysis of antibody responses in BCG intravenous vaccination against Mycobacterium tuberculosis in non-human primates show a potential protective role for IgM.
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.
The extreme diversity of the human immune system, forged and maintained throughout evolutionary history, provides a potent defense against opportunistic pathogens. Liston and colleagues review the current state of play in the field, identify the key unknowns in the causality of immune variation and identify the multidisciplinary pathways toward an improved understanding.
Whether COVID-19 during pregnancy affects the health of children is unclear. Data now show that SARS-CoV-2 infection of mothers can prime the fetal immune response indirectly even when the virus does not infect the fetus.