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Patients with partial recombination-activating gene (RAG) deficiency (pRD) present variable late-onset autoimmune clinical phenotypes. Walter and colleagues identified a restricted primary B cell antigen receptor repertoire enriched for autoreactivity and clonal persistence in pRD. They described dysregulated B cell maturation with expansion of T-bet+ B cells revealing how RAG impacts stringency of tolerance and B cell fate in the periphery.
Patients with cancer undergoing anti-PD-1 immune checkpoint blockade can experience immune-related adverse effects. Wherry and colleagues examined the immunity elicited upon immunization of patients with cancer and report that anti-PD-1 immunotherapy dynamically affects influenza vaccine-induced immune responses.
Mackay and colleagues show that distinct programs of tissue residency are induced in CD8+ and CD4+ TRM cell subsets, a difference attributable to the activity of the transcription factor Runx3.
Acton and colleagues examine the mechanics of lymph node swelling during the course of an immune response. They find tissue tension regulates fibroblastic reticular cell (FRC) proliferation during lymph node expansion and that podoplanin (PDPN)–CLEC-2 signaling in FRCs regulates this process, which in turn regulates T cell activation.
Xue and colleagues show that Tcf1 and Lef1 recruit the genome organizer CTCF to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8+ T cells undergoing homeostatic proliferation.
The deacetylase SIRT1 regulates IRF3/IRF7-mediated antiviral interferon signaling. Here the authors show that SIRT1 deactylates the DNA-binding domain resulting in liquid–liquid phase separation of IRF3/IRF7 and that this signaling is inhibited in aging, an effect that can be reversed with a SIRT1 agonist to restore antiviral response.
Heissmeyer and colleagues show that TCR stimulation-induced cell death is controlled by N6-methyladenosine (m6A) modification of Orai1 and Ripk1 mRNAs. m6A is deposited by a ‘writer’ complex of Wtap and the N6-methyltransferase and bound by the ‘reader’ protein Ythdf2. T cells lacking Wtap exhibit enhanced Ca2+ entry in response to TCR ligation and decreased survival due to activation-induced cell death.
Predicting which patients will respond to checkpoint blocking therapies is a major challenge. Here the authors score the epigenetic imprinting of T cell responsiveness to type 1 interferons and use this information to predict response to anti-PD1 therapy and long-term survival of cancer patients.
Sun and colleagues describe that the secretion of interleukin-33 is dependent on a p40 N-terminal fragment of gasdermin D, whose generation is independent of inflammatory caspase-1 and caspase-11.
Abramson and colleagues show that Aire+MHCII+ ILC3s sense, internalize and present Candida albicans and modulate the induction of C. albicans-specific TH17 cells.
LAG3 inhibits T cell activation, but exactly how it does so has been unclear given a lack of structural information. Here the authors provide the crystal structure of the human and mouse LAG3 ectodomains, showing how they interact with known ligands and antibodies.
Lanzavecchia and colleagues use single-cell B cell receptor sequencing to examine the clonal structure, stability and dynamics of the B cell repertoire and the relationship between memory B cells and newly generated plasma cells in humans.
Skin Treg cell crosstalk with hair-follicle stem cells (HFSCs) can control hair regrowth. Here the authors show that glucocorticoid receptor signaling in skin Treg cells induces TGF-β3, which in turn facilitates HFSC proliferation.
Vahedi and colleagues show that TCF-1 promotes T cell development by minimizing the spatial distance between regulatory elements that are located within insulated neighborhoods in progenitor cells and are required for the expression of T cell genes.
Extracellular microenvironments are more acidic upon tissue damage or in tumors. Xavier and colleagues identify a role for the pH-sensitive, G protein-coupled receptor GPR65 in multiple aspects of immune cell lipid metabolism, disruption of which leads to chronic inflammatory responses.
A broadly neutralizing antibody (bnAb) response is required to combat SARS-CoV-2 variants of concern (VOCs). The authors isolated and characterized a large panel of sarbecovirus bnAbs from vaccinated individuals who had recovered from COVID-19, finding that many of these antibodies were able to neutralize all VOCs, including Omicron, and demonstrate prophylaxis in mice infected with diverse sarbecoviruses.
Breed et al. identify a subset of thymic SIRPα+ cDC2 dendritic cells that express CD301b, induced by type II cytokines, and high amounts of MHC-II. They find that the deletion of these cells can alter thymic CD4-single-positive repertoires, suggesting that they contribute to thymic tolerance.
Mirchandani and colleagues show that tissue hypoxia alters the number and phenotype of circulating monocytes and their differentiation into lung macrophages, with important implications for the resolution of inflammation in the lung.