Manakkat Vijay GK, Ramaswami B, Gierlack S
… +11 more, Pease NA, Gerges P, Chen D, Thakkar K, Mena Hernandez L, Keshari S, Xu H, Salomonis N, Das J, Rothstein DM, Singh H
Nat Immunol
· 2026 Jun · PMID 42010057
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Germinal center B cell responses are defined by many positive regulators of affinity maturation, but few components that restrain clonal dominance, notably Nr4a1, are known. We reveal an unsuspected role for BLIMP1 (Prdm...Germinal center B cell responses are defined by many positive regulators of affinity maturation, but few components that restrain clonal dominance, notably Nr4a1, are known. We reveal an unsuspected role for BLIMP1 (Prdm1)-a plasma cell determinant-as a feedback regulator of affinity maturation. Single-cell RNA and B cell receptor (BCR) sequencing showed that B cell-specific Prdm1 loss drives an exaggerated germinal center reaction with larger clones, increased somatic hypermutation and greater clonal dominance, independent of Nr4a1. Single-cell chromatin profiling with base-resolution modeling indicated that Blimp-1 represses expression of BCR-signaling genes, gating chromatin accessibility at interferon-stimulated response elements, Ets-interferon regulatory factor composite elements, nuclear factor kappa B and Oct motifs. In the absence of BLIMP1, enhanced BCR-signaling augments activities of transcription factors that promote G1-S transition during light zone (LZ) selection and fuel dark zone (DZ) expansion. Thus, BLIMP1 attenuates BCR signaling and constrains the LZ to DZ transition, fine-tuning clonal competition, thereby maintaining repertoire diversity.
Tumor cells are highly dependent on branched-chain amino acids, which can activate mechanistic target of rapamycin complex 1, but the downstream catabolite branched-chain α-keto acids (BCKAs) are not well studied in this...Tumor cells are highly dependent on branched-chain amino acids, which can activate mechanistic target of rapamycin complex 1, but the downstream catabolite branched-chain α-keto acids (BCKAs) are not well studied in this context. Here, using clinical samples and genetically engineered mouse tumor models, we showed that tumor-derived BCKAs are secreted actively into the tumor microenvironment (TME) where they reprogram tumor-associated macrophages (TAMs) to promote tumor progression. Through genome-wide CRISPR screening, we identified Notch2 as a direct molecular target of BCKAs. BCKAs activate Notch signaling by binding to and stabilizing cleaved Notch2, functionally reprogramming TAMs and fostering an immunosuppressive TME. Mutation of the BCKA-binding site in Notch2 abolishes this effect in vivo. Together, these findings identify BCKAs as signaling metabolites that mediate tumor immunosuppression through direct sensing by Notch2.
Tajima M, Hao H, Zhang B
… +27 more, Matsuoka Y, Sonomura K, Imami K, Isobe Y, Maeda R, Lin YH, Shimba A, Kato R, Costa Cruz PH, Washizu S, Ikejiri Y, Morinibu A, Barker CS, Seita J, Wu Y, Ito S, Narushima S, Nakano R, Maruya M, Kobayashi W, Narayanan SSP, Shaheen J, Neyama H, Yamada KI, Arita M, Sugiura Y, Fagarasan S
Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8 T cell metabolism remain unknown. Here, we found that even tempora...Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8 T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in phospholipids sensitive to peroxidation and depletion of antioxidants, affecting the survival and function of CD8 T cells. Under oxidative stress, CD8 T cells utilized the xanthine salvage pathway to produce guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining lymph nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8 T cells persists long after restoration of a balanced diet, and manifests as vulnerability to ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.
Central and peripheral immune tolerance depend on distinct transcriptional programs orchestrated by autoimmune regulator (AIRE) and FOXP3, respectively. AIRE promotes the expression of peripheral tissue antigens in medul...Central and peripheral immune tolerance depend on distinct transcriptional programs orchestrated by autoimmune regulator (AIRE) and FOXP3, respectively. AIRE promotes the expression of peripheral tissue antigens in medullary thymic epithelial cells for negative selection of autoreactive T cells, whereas FOXP3 enforces the immune-suppressive program of regulatory T cells. Although their immunological roles are well established, the molecular mechanisms by which AIRE and FOXP3 engage the genome and regulate transcription have long been unclear. Recent structural, biochemical and genomic work has revealed an unexpected shared principle: both FOXP3 and AIRE form homomultimers that function as chromatin organizers. Despite functioning in different immunological contexts and possessing distinct modes of genome interaction, both proteins leverage and reinforce pre-existing chromatin landscapes to coordinate broader gene expression programs. In this Review, we summarize recent advances and emerging mechanistic insights into FOXP3 and AIRE, focusing on their multimerization, interactions with repetitive DNA and enhancers and roles as architectural regulators that shape transcriptional programs essential for immune tolerance.
CD4⁺ helper T (T) cells consist of multiple functional subsets defined by specific effector cytokines and transcription factors. Recently, single-cell transcriptomic analyses have revealed possible existence of additiona...CD4⁺ helper T (T) cells consist of multiple functional subsets defined by specific effector cytokines and transcription factors. Recently, single-cell transcriptomic analyses have revealed possible existence of additional populations. Here we identify a unique CD4⁺ T cell subset in mouse and human colitis characterized by high levels of granzyme K (Gzmk) expression, designated as TK cells. These cells exhibit unique transcriptional signatures, with minimal expression of classical T-defining factors but rather prominent Eomesodermin (Eomes) expression. Notably, TK cell differentiation is independent of T1, T2 and T17 lineages in colitis. EOMES is both necessary and sufficient for TK cell induction, by directly driving the expression of Gzmk and associated effector molecules. Genetic ablation of Eomes ameliorates intestinal immunopathology in a T cell-induced colitis model. The TK transcriptional program seems to be conserved across species and in diverse disease contexts. Our findings establish TK cells as a distinct T cell subtype, and the EOMES-TK axis may serve as a potential therapeutic target in inflammatory diseases.
Nat Immunol
· 2026 May · PMID 41917203
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Tissue-resident macrophages populate nearly all organs, where they adopt tissue-specific roles essential for immune defense, tissue development and homeostasis. Their dysfunction contributes to inflammation, cancer and o...Tissue-resident macrophages populate nearly all organs, where they adopt tissue-specific roles essential for immune defense, tissue development and homeostasis. Their dysfunction contributes to inflammation, cancer and other diseases. Whether a dedicated macrophage population operates within the extensive vascular network, one of the body's largest and most widely distributed tissues, has remained unknown. Here, using high-resolution spatiotemporal live imaging in zebrafish embryos, we identify a distinct population of macrophages residing within blood vessels, termed blood vessel-resident macrophages (bMΦs), with conserved features in mice. bMΦs patrol the bloodstream, clear foreign particles and unfit cells, and act as first responders to endothelial damage. bMΦs emerge directly from axial vessels through an atypical endothelial-to-macrophage transition that is independent of Runx1 and Csf1r. Our findings reveal a previously unrecognized macrophage population dedicated to vascular immune surveillance, uncovering mechanisms that preserve blood and vessel integrity and offering potential therapeutic avenues for bloodborne and vascular diseases.
Sex differences in immune function arise from sex chromosome complement, which drives differential expression and activity of X-linked genes in immune cells, and gonadal steroids that transcriptionally regulate innate an...Sex differences in immune function arise from sex chromosome complement, which drives differential expression and activity of X-linked genes in immune cells, and gonadal steroids that transcriptionally regulate innate and adaptive immune cells through their respective receptors. These fundamental differences shape divergent outcomes between male and female individuals in viral and bacterial infections, post-acute infection syndromes and vaccine responses throughout the lifespan. Understanding these sex-specific immune mechanisms represents a critical frontier for developing novel therapeutic targets and advancing personalized medicine.
Xiao T, Chen X, Song NJ
… +25 more, Brown RJ, Ma A, Mandula JK, Yousif A, Wang Y, Le MQM, Li J, Gao F, Weaver B, Chen HY, Lay FY, Sundi D, Velegraki M, Weltge P, Merchant JL, Rubinstein MP, Oestreich KJ, Lio CJ, Ghoneim HE, Li X, Theodorescu D, Xin G, Ma Q, Cui W, Li Z
Nat Immunol
· 2026 Apr · PMID 41896465
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Full text
Progenitor CD8 T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined...Progenitor CD8 T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8 T cell effector differentiation. ZFP148-deficient CD8 T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with Zfp148 controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8 T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower ZNF148 expression in tumor-infiltrating CD8 T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8 T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.