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Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Dysregulated immune features in a patient with a homozygous loss-of-function mutation in PDCD1 suggest that IL-6, IL-23, STAT3 and RORγT might be potential targets for treatment of PD-1 blockade-induced autoimmunity.

An increasing number of studies have highlighted novel aspects of the differentiation and function of T follicular helper (T_FH) cells. Tangye et al. discuss these recent findings with a particular focus on the role of human T_FHcells in disease pathogenesis.

T cells of the immune system mount antiviral responses, but if a response fails, a chronic viral infection can develop. It now seems that a T-cell subset in lymphoid immune tissues can control chronic infection. See Letters p.412 & p.417

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Neutrophils and B cells are thought to specialize in driving innate and adaptive immune responses to infection. New data suggest that these cells may also communicate in the splenic marginal zone to drive T cell–independent antibody responses.

Prolonged physical interaction between helper T cells and antibody-producing B cells is crucial for efficient immune responses. Mutations in a protein that underlies this process cause human disease.

IL-27RA–IL-27 has a critical role in the immunity to EBV, and this defence is hijacked by Epstein–Barr virus to promote the expansion of infected transformed B cells

Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.

Cross-protective responses across all strains of influenza virus (IAV, IBV and ICV) are a key goal of universal vaccines against influenza. Kedzierska and colleagues identify cytotoxic T cells present in blood and lungs of healthy people that are directed against all strains of influenza virus.

The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8⁺ T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.

The sensing of viable pathogens by the receptor TLR8 on human monocytes provides key signals that initiate the differentiation of naive CD4⁺ T cells into follicular helper T cells. Targeting TLR8 might represent a novel approach for improving immunity following vaccination.

Primary immunodeficiency can predispose patients to mycobacterial disease. Casanova and colleagues identify novel human mutations in the enzyme SPPL2A that result in selective accumulation of CD74 in a dendritic cell subset and lead to their death and the failure to mount effective T_H1 responses.

A20, encoded by TNFAIP3, is a negative-feedback inhibitor of NF-κB. Grey and colleagues identify natural human variants of TNFAIP3, which lower A20 activity and increase autoinflammatory responses. These alleles were inherited by descendants of Denisovans who crossed the Wallace Line to inhabit Oceania.

Co-stimulatory second signals delivered through TLRs or CD40 rescue antigen-stimulated B cells from metabolic dysfunction and apoptosis. This identifies a critical time-limited window during which B cells integrate sequential signals to successfully initiate humoral immunity.

Zinc is important for normal immunity but its mechanistic actions are poorly understood. Hambleton and colleagues identify defects in Zn²⁺ transport that underpin a novel human immunodeficiency characterized by loss of mature B cells.

Lymphocyte function is regulated by phosphatidylinositol-dependent pathways. Uzel and colleagues identify a cohort of immunodeficient patients with hyperactive phosphatidylinositol-3-OH kinase activity due to mutant p110δ subunits, which results in enhanced senescence of cells of the immune system.

High-affinity and isotype-switched antibodies arise from germinal center reactions. Goodnow and colleagues identify the Rho guanine nucleotide–exchange factor DOCK8 as being essential for sustained B cell immune synapse formation in germinal centers and mature antibody responses.

Memory B cells need to be reactivated to produce high affinity antibody responses on subsequent antigen encounters. Here the authors show that memory B cells localise to lymph node subcapsular proliferative foci (SPF), which have distinct properties from the germinal centre, for rapid expansion and the induction of B memory responses.

PRMT1 is an arginine methyltransferase involved in a variety of cell functions. Here the authors delete PRMT1 specifically in mature B cells to show the importance of arginine methylation for B cell proliferation, differentiation and survival, and thereby for humoral immunity.

Invariant NKT cells elicit the rapid release of cytokines. Two papers by Leadbetter and Vinuesa and colleagues show that these cells can also provide direct help to B cells to elicit rapid antibody responses.

The COVID Human Genetic Effort examines the molecular, cellular and immunological determinants of the various SARS-CoV-2-related disease manifestations by searching for causal errors of immunity.