Jabara HH, McDonald DR, Janssen E
… +28 more, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock D, Manis J, Keles S, Ceja R, Chatila TA, Geha RS
Regulatory factor X 7 (RFX7) nonsense mutations have been found in different human B cell malignancies. We therefore set out to study the role of RFX7 in B cell activation and lymphomagenesis. Here we show that RFX7 trun...Regulatory factor X 7 (RFX7) nonsense mutations have been found in different human B cell malignancies. We therefore set out to study the role of RFX7 in B cell activation and lymphomagenesis. Here we show that RFX7 truncations cause loss-of-function and dominant-negative effects. Moreover, low RFX7 mRNA levels correlate with worse diffuse large B cell lymphoma prognosis. Accordingly, Rfx7 deletion in B cells accelerates pathogenesis in mouse Bcl6- and p53-loss-driven B cell lymphoma models. Rfx7-deficient B cells exhibit increased Myc activity and enhanced germinal center B cell and plasmablast responses. These alterations are reverted by Myc haploinsufficiency, which provides partial protection from nonsymptomatic p53Rfx7 B cell lymphoma, but does not prevent detrimental Myc deregulation in aggressive disease. Deletion of Aicda, which favors genomic alterations in activated B cells, limits lymphoma development in the p53Rfx7 double-hit mouse model. These results indicate that Rfx7 represses B cell activation, Myc activity, and Myc- and activation-induced cytidine deaminase (AID)-dependent pro-lymphomagenic processes.
Autoimmune diseases can affect the lungs, and the mechanisms used to prevent autoimmune lung disease are incompletely understood. Recent studies in the thymus have identified unique populations of medullary thymic epithe...Autoimmune diseases can affect the lungs, and the mechanisms used to prevent autoimmune lung disease are incompletely understood. Recent studies in the thymus have identified unique populations of medullary thymic epithelial cells (mTECs) called mimetic cells that transcriptionally mimic peripheral epithelial populations. These mimetic cells have important functions in the thymus in immune tolerance. Here, we used a mouse line with thymic-specific deletion of Runt-related transcription factor 1 (Runx1) to identify a new mimetic cell akin to alveolar type 2 (AT2) lung epithelial cells. AT2 mTECs express surfactant genes, and with Runx1 deletion AT2 mTECs expand, resulting in a loss of AIRE mTECs and defects in T cell selection. RUNX1 suppresses AT2 mTECs by inhibiting epidermal growth factor receptor signaling. Together, our results identify a thymic mimetic cell type that mimics lung AT2 epithelial cells, further uncovering unrealized epithelial diversity in the thymus.
The perinatal period of immune ontogeny reflects prenatal, maternal and postnatal cues that converge to establish durable immune trajectories. Fetal and infant immunity follows distinct, ontogeny-specific programs optimi...The perinatal period of immune ontogeny reflects prenatal, maternal and postnatal cues that converge to establish durable immune trajectories. Fetal and infant immunity follows distinct, ontogeny-specific programs optimized for tissue protection, tolerance and rapid effector function. Herein, we integrate recent insights into prenatal hematopoiesis, tissue seeding by innate and adaptive lymphocytes, and the establishment of immune specialization across barriers and systemic compartments. We examine how cellular and humoral factors in blood, tissues and/or breast milk calibrate immune development, and how postnatal microbial colonization and environmental exposures further refine immune function in a tissue- and time-dependent manner. Together, these findings redefine early life as a critical window during which immune set points are established, with lasting immunological imprinting linked to host defense, vaccine responsiveness and risk for atopy. A mechanistic understanding of these processes provides a framework for rational, age-adapted strategies to promote immune health across the life course.
Jena KK, Qu P, Baracco L
… +32 more, Saghaei S, Keerti, Allahyari Z, Boehmer D, Mitchell M, Dillen CA, Li HY, Liu E, Poli V, Dufies O, Hoytema van Konijnenburg DP, Spreafico R, Bi C, Hall R, Kruppa MD, Ma Z, Gravitte A, Lowman DW, Ensley HE, Marty P, Boyer L, Collomp R, Williams DL, Ma VP, Lee PY, Nigrovic PA, Karp JM, Elledge SJ, Wesemann DR, Wu Y, Frieman M, Zanoni I
Nat Immunol
· 2026 Jun · PMID 42174265
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The activation of pattern recognition receptors (PRRs) orchestrates inflammation and regulates adaptive immunity. To test whether tuning inflammation through PRR stimulation enhanced the efficacy of mRNA vaccines, we com...The activation of pattern recognition receptors (PRRs) orchestrates inflammation and regulates adaptive immunity. To test whether tuning inflammation through PRR stimulation enhanced the efficacy of mRNA vaccines, we combined an mRNA-based vaccine generated against the ancestral spike protein of SARS-CoV-2 with mannadjuvant, a formulation of fungal mannan and aluminum hydroxide targeting the PRR dectin-2. In mice and non-human primates, mannadjuvant increased the magnitude and durability of the response elicited by the mRNA-based vaccine, and it also led to the induction of neutralizing antibodies directed against variants of concern with a high escape capacity, overcoming antigenic imprinting. Mechanistically, prolonged type I interferon (IFN) production and potentiated interleukin-1 (IL-1) signaling locally within the draining lymph node in mice or in human cells were necessary and sufficient to exert the effect of mannadjuvant. Our data indicate that antifungal PRRs can be harnessed to create more potent and durable mRNA-based vaccines.
Dong H, Ray A, Rotter LK
… +20 more, Wang J, Grabski I, Mewada H, Wang L, Huang K, Tian Y, Meylan M, Barlow G, Yu C, Raundhal M, Yoon SH, Nakhawa S, Ding L, Zhao JJ, Matulonis UA, Foretz M, Wucherpfennig KW, Irizarry RA, Wein MN, Glimcher LH
Nat Immunol
· 2026 Jun · PMID 42162294
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Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of...Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, whereas SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant high-grade serous ovarian carcinoma, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2 and -3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-γ, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.
Courau T, Jaszczak RG, Samad B
… +21 more, Flynn E, Chew NW, Reeder GC, Tsui J, Teklu S, Pass LF, Edwards AW, Naser M, Ray A, Wismer H, Bunis D, Lupin-Jimenez L, Gavil NV, Masopust D, Graham JP, Skelly DA, Vesco X, Liu ET, Fragiadakis GK, Combes AJ, Krummel MF
Nat Immunol
· 2026 Jun · PMID 42156893
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Mouse models are frequently used to develop treatments for human cancer. However, the degree to which their tumor microenvironments (TMEs) are synonymously assembled is particularly poorly characterized. Through systemat...Mouse models are frequently used to develop treatments for human cancer. However, the degree to which their tumor microenvironments (TMEs) are synonymously assembled is particularly poorly characterized. Through systematic immunoprofiling of 15 commonly used mouse models, we found that most murine TMEs recapitulate the composition of poorly infiltrated human tumors, extensively biased toward high macrophage densities. We discovered substantial species-specific biases of chemokine expression networks known to drive TMEs assembly, together with discoordinated frequencies of T and myeloid cell subtypes. Even with variable alignment, conserved cell-type-specific gene expression programs emerged across species and cohorts. Dissecting the coordinated T cell-myeloid gene expression programs revealed a conserved axis between interferon-responsive myeloid states and ongoing T cell cytotoxicity that transcends tissue of origin and predicts clinical outcome. Collectively, this work provides a practical atlas outlining both the hazards and opportunities of using mice to model human cancer.