Articles in 2021

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.

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.

Adipose tissue-resident regulatory T (T_reg) cells are important for maintaining normal metabolic function and adiposity. Li and colleagues demonstrate that insulin signaling directly controls adipose T_reg cell development and functionality

Regulatory T cells are functional in a broad-spectrum systemic autoimmune disease and are capable of suppressing innate and adaptive immune responses, reversing established tissue inflammation and enabling long-term restoration of immunological health.

Tissue-resident memory T (T_RM) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T_RM cells are generated dictates their properties and is in turn defined according to T_RM-cell-intrinsic sensitivity to signaling via the cytokine TGFβ.

The beta variant (B.1.351) is to date the most resistant to neutralization of the SARS-CoV-2 variants. Using nonhuman primates, Seder and colleagues demonstrate that double vaccination with a high dose of the lipid nanoparticle vaccine mRNA-1273 protects against infection with the beta variant.

T follicular helper (T_FH) cells are important for the generation of effective antibody responses. Yu and colleagues find that T_FH cells are exceptionally sensitive to death by ferroptosis and that this process is regulated by the activity of the selenoenzyme GPX4.

Khazaie and colleagues show that TCF-1 cooperates with FOXP3 to differentially regulate independent suppressive activities of T_reg cells. T_reg cell–specific deficiency of TCF-1 increases tumor load in mice predisposed to polyposis. Functionally, TCF-1-deficient T_reg cells suppress viral antigen–specific CD8⁺ T cell cytotoxicity, but TCF-1-deficient T_reg cells fail to suppress T_H1 or T_H17 polarization of conventional CD4⁺ T cells. This scenario leads to increased cytokine-mediated tissue inflammation but still restrains the adaptive antitumor cytotoxicity.

Zhang and colleagues identify a role for cell death by glutathione peroxidase 4 (GPX4)-regulated ferroptosis in neutrophils from patients with systemic lupus erythematosus, which is triggered by type I interferons and autoreactive antibodies and contributes to lupus pathogenesis. Inhibiting accumulation of oxidative mediators by GPX4 suppresses ferroptosis.

Lucas and colleagues describe loss-of-function variants in the X-linked ETS transcription factor ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD)-like features.

Wherry and colleagues examine whether exhausted T cells (T_EX) can differentiate into functional memory T cells (T_MEM) when chronic antigen is withdrawn. Using the chronic LCMV infection mouse model, they show that ‘recovering’ T_EX cells (REC-T_EX) only partially recover immunophenotypic and functional characteristics of T_MEM cells. The epigenomic status of REC-T_EX cells more closely resembles that of T_EX cells, and, upon rechallenge, the REC-T_EX cells were still compromised in their ability to respond to virus.