Research articles

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.

ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.

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.

Scheiermann and colleagues show that circadian clocks control the infiltration of dendritic cells into skin lymphatics in mice and humans, with a peak migration to the lymph nodes during the rest phase.

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.

Many babies have now been born to mothers who were exposed to SARS-CoV-2 during their pregnancy. Here the authors look at the effect of this exposure on the immunology of human neonates, showing immune changes and increased neonatal cytokine responses despite limited evidence of vertical transmission.

Pediatric COVID-19 can be associated with subsequent multisystem inflammatory syndrome in children (MIS-C), but how these pathologies are related or differ is unclear. Here the authors compare and contrast pediatric COVID-19 and MIS-C immunophenotypes using SARS-CoV-2 antibody fingerprinting proteomics.

Elemento, Melnick and colleagues examine the chromatin and transcriptional changes that occur during differentiation of human primary B cells into antibody-secreting cells. In naive B cells, the transcription factor OCT2 is preloaded at high-affinity super-enhancer sites present in repressed ‘silent’ chromatin; upon activation, OCAB is recruited to these regions, where it facilitates arrays of OCT2 binding to lower-affinity octamer motifs, leading to active formation of germinal center B cell-specific super-enhancers.

Adipose tissue macrophages are intimately involved with adipocytes to orchestrate whole-body energy metabolism. Qiu and colleagues show that myeloid-specific deletion of the homeobox protein IRX3 protects against diet-induced obesity, excessive proinflammatory cytokine secretion and metabolic diseases via increasing adaptive thermogenesis.

Traumatic brain injury and stroke are commonly complicated by systemic infections, which impede recovery and lead to poor clinical outcomes. Using a mouse model, McGavern and colleagues show systemic microbial infections impair central nervous system revascularization and repair by a mechanism involving type I interferon signaling.

Understanding the mechanistic basis of vaccine efficacy is crucial to the development of next-generation vaccines. Sekaly and colleagues find that activation of the transcription factor CREB1 by the RV144 HIV-1 vaccine underpins the induction of robust adaptive immunity.

Fiancette et al. utilize models of inducible transcription factor deletion in mature tissue-resident ILCs to reveal complementary and competing transcriptional networks that determine ILC3 phenotype and functional capacity.

Romagnani and colleagues discover an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.

Blind mole rats are small rodents characterized by an exceptionally long lifespan and resistance to both spontaneous and induced tumorigenesis. Gorbunova and colleagues show that a transposon-triggered innate immune response confers cancer resistance to the blind mole rat.

IL-33 plays a central role in type II immune responses and is generally thought to be released following cellular damage and processed extracellularly. Rothenberg and colleagues describe a new ripoptosome pathway that is assembled following exposure to various unrelated environmental allergens and that processes IL-33 into an active form intracellularly.

Mucosal surfaces of the respiratory tract are the first sites of entry and defense against SARS-CoV-2. Di Santo and colleagues perform paired analysis of the nasopharyngeal and systemic immune responses of SARS-CoV-2-infected patients and demonstrate distinct compartmentalization of immunity and shifts in the microbiome.

ILCs are considered preformed effector cells. Gasteiger and colleagues report that ILC1s undergo effector differentiation after lineage commitment. Hobit⁺ ILC1s emerge as cKit⁺TCF-1^hi cells that generate tissue-specific helper- and cytotoxic-like cells along a Hobit-dependent trajectory.