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Here the authors show that mice exposed to a variety of pathogens initially have impaired innate type 2 responses to lung allergens, but reactivity resets over time, indicating that microbial experience does not stably inhibit innate immunity to allergens.
Notch signaling is required for T cell development. Georgopoulos and colleagues identify an enhancer that specifically boosts Notch1 expression in early thymic progenitors through the DN3 stage, expanding the less committed multipotent progenitors and preparing these cells for faithful lineage commitment.
Durable antibody-mediated responses require long-lived plasma cells; however, these cells are difficult to identify. Hai Qi and colleagues now phenotypically identify these cells and show their heterogeneity.
Farrar and colleagues perform an extensive analysis of Ncor1/2 function in B cell development. Loss of both genes results in defective pre-BCR signaling, increased accessibility of STAT5 chromatin motifs and inappropriate Rag gene expression, leading to accelerated leukemic transformation.
Here, the authors use single-cell multiomics and profiling of mitochondrial mutations as endogenous barcodes to show that human adaptive NK cells induced by CMV persist as clonal expansions that inherit clone-specific epigenetic profiles.
Daniel, Yost, Hsiung, et al. generate a single-cell multiomic atlas of T cell exhaustion in chronic viral infection, which reveals molecular programs of exhausted T cell subsets, identifies divergent clonal exhausted T cell differentiation trajectories and nominates TCR signal strength as a driver of clonal fate.
Wherry and colleagues provide a comparative analysis of paired single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin sequencing profiles of CD8+ T cells in acute and chronic lymphocytic choriomeningitis virus infections, identifying new features about Tex cell subsets and epigenetic differences from acutely infected precursors seen at early time points in infection.
CD40 is typically understood as a costimulatory molecule. Here, the authors show CD4+ T cell-induced CD40 signaling in conventional type 1 dendritic cells results in complicated gene expression that can enhance CD8+ T cell priming by various underappreciated and independent mechanisms.
Lai and colleagues show that the RNA helicase DDX5 mediates the alternative splicing of the IL-36R mRNA in keratinocytes and modulates skin inflammation downstream of IL-17D signaling.
Wen and colleagues show that the transmembrane protein SUSD2 is a specific negative regulator of CD8+ T cells activation in the tumor environment by interacting with IL-2 receptor α and interfering with IL-2 binding to the receptor.
Endosomal TLR7 and TLR9 recognize RNA and DNA ligands, respectively, and both signal via MyD88 yet appear to play opposing roles in autoimmunity. Shlomchik and colleagues examine this TLR ‘paradox’, reporting that TLR9 has two protective functions, including an as yet unidentified additional MyD88-independent signaling pathway that confers protection against autoimmunity.
Naive T cells are quiescent but undergo dynamic changes upon antigenic activation. Li and colleagues show that upregulation of tRNA methyltransferase complex TRMT61A–TRMT6 and N1-methyladenosine modification of tRNAs contribute to accelerated mRNA translation efficiency, in particular that of MYC protein, and are required for rapid T cell proliferation.
Pace and colleagues assessed the antibody titers, B cell and T cell memory response against SARS-COV-2 in mRNA-vaccinated individuals to show that reduced antibody titers combined with a distinctive memory T cell profile in low vaccine responders correlated with breakthrough infection.
Henao-Mejia and colleagues provide a detailed characterization of the 3D genome architecture of ILCs and demonstrate that ILC2 development and progression of allergic inflammation are controlled by a unique 3D DNA topology at the Id2 locus.
Roncagalli and colleagues use time-resolved high-throughput proteomic analyses to provide a comprehensive picture of the impact of ligand affinity on early T cell receptor signaling.
Type I interferons have been described to have protumor or antitumor functions depending on context. Here the authors show a protumor function for type I interferons in that they promote cancer stem cells by upregulating the chromatin remodeling factor KDM1B.
Osteoclastic bone destruction is mediated by factors such as RANKL elaborated by tissue-destructive fibroblasts. Takayanagi and colleagues identify the transcription factor Ets1 as a major regulator of these pathogenic cells.
The inhibitory receptor CTLA-4 recognizes two ligands on opposing antigen-presenting cells, CD80 and CD86. Sansom and colleagues show CTLA-4 captures ligands by transendocytosis, whereupon low-affinity CD86 releases CTLA-4 at low pH to promote CTLA-4 recycling; however, high-affinity CD80 remains bound and targets CTLA-4 for ubiquitination and destruction.
The STAT3 pathway is activated in B cells by interleukin-6 and interleukin-21; however, methylation of Lys140 prevents its dephosphorylation and deactivation. Yin et al. report a noncanonical role for the histone demethylase Jmjd1c in demethylating phosphorylated STAT3, thereby terminating B cell activation and limiting plasma cell generation and potential B cell-mediated autoimmunity.