Tuberculosis (TB) remains a global health issue and leading cause of death. Understanding the immune response to Mycobacterium tuberculosis infection is critical to advance TB control. Although immune factors involved in...Tuberculosis (TB) remains a global health issue and leading cause of death. Understanding the immune response to Mycobacterium tuberculosis infection is critical to advance TB control. Although immune factors involved in protection against TB have long been identified, these cannot predict the efficacy of TB vaccines, nor which individuals will control the infection or progress to active TB disease. This is especially challenging given the complexity of M. tuberculosis infection states and the breadth of TB disease severities, which is increasingly apparent from basic, clinical and translational research. Here, we discuss the evolving spectrum of M. tuberculosis infection outcomes and TB disease, how the host immune response determines and unfolds across this spectrum and how the natural diversity of M. tuberculosis contributes to this complexity. Integration of these new concepts with fast-evolving systems immunology approaches holds great potential to inform the design of novel strategies to control TB.
Kerndl M, Musiejovsky L, Komljenovic A
… +26 more, Lam HS, Vogel A, Bausbacher T, Riedl CJ, Sango R, Matejovicova L, Dobrijevic A, Oberbichler L, Hofmann M, Kieler M, Quemada Garrido L, Perko Budja LV, Brunner JS, Cairns JL, Cheng P, Kitt K, Isaguirre C, Köcher T, Klavins K, Rattei T, Hametner S, Blüml S, Hopf C, Sheldon RD, Sharif O, Schabbauer G
Nat Immunol
· 2026 Jul · PMID 42151478
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Inflammatory responses are associated with recruitment of monocyte-derived cells (Mdcs) into tissues. Although tissue-specific Mdc reprogramming is well established, how Mdc infiltration alters tissue metabolism remains...Inflammatory responses are associated with recruitment of monocyte-derived cells (Mdcs) into tissues. Although tissue-specific Mdc reprogramming is well established, how Mdc infiltration alters tissue metabolism remains unclear. Here, using a mouse neuroinflammation model coupled with genetic fate mapping, metabolomics and metabolite imaging, we identify that central nervous system (CNS) Mdc infiltration is associated with substantial metabolic changes and assign disease-linked metabolites therein. In particular, we found that increased arginine catabolism driven by lesion-associated arginase 1 (Arg1)-expressing Mdcs promoted oxidative damage, lipid accumulation and Mdc dysfunction. Genetic ARG1 deficiency within Mdcs during neuroinflammation increased extracellular arginine and was associated with rewiring of the CNS metabolic landscape, including attenuated disease-linked metabolites. This was accompanied by enhanced Mdc-driven anti-inflammation, regulatory T cell expansion and improved disease outcome. Opposing effects were observed following dietary arginine deficiency. Together, our work highlights key roles for Mdcs in CNS metabolism and reveals the pleiotropic beneficial effects of arginine in neuroinflammation.
Lebon S, Habshush Menachem A, Davidzohn N
… +19 more, Katz A, Wigoda N, Braun T, Yahalomi D, Rotkopf R, Holiar V, Dadosh T, Levin-Zaidman S, Dezorella N, Goliand I, Kupervaser M, Leebhoff S, Blumberger N, Hoffman D, Grunewald M, Levin Y, Haberman Y, Hofree M, Biton M
Nat Immunol
· 2026 Jul · PMID 42120792
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Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsi...Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsic immune mechanism whereby Lgr5 ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled S. enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via apoptosis-associated Speck-like protein containing a CARD (ASC, encoded by Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from patients with Crohn's disease. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.
Wu YC, Yang SF, Lee YT
… +20 more, Chou MW, Lin SY, Wang YC, Su SY, Hsu CL, Chang NW, Huang YJ, Juan YH, Lu HH, Chen CY, Wang YF, Lee PJ, Kao HJ, Wu PS, Lin MH, Hsu LC, Chiu YL, Chen SY, Yu CJ, Tsai HC
T cell exhaustion represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally exhausted state. He...T cell exhaustion represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally exhausted state. Here we used an epigenetic drug screen and identified bromodomain and extra-terminal motif inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells (T) from malignant pleural effusions in patients with lung cancer. Transcriptomics, metabolomics and ATAC-seq analyses revealed that BETis reinvigorate T cells by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (ODC1), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated that BETis reduced terminal T while promoting progenitor T through activation of the MYC-ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic-metabolic approach to enhance T plasticity and offer insights for novel cancer immunotherapies.
Sharma P, Guo A, Poudel S
… +12 more, Boada-Romero E, Verbist KC, Palacios G, Immadisetty K, Chen MJ, Haydar D, Mishra A, Peng J, Babu MM, Krenciute G, Glazer ES, Green DR
Nat Immunol
· 2026 Jun · PMID 42098363
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Yang-Fischer R, Shearer A, Leão FB
… +5 more, Pascual-Gonzalez I, Han A, Castellanos-Rubio A, Bhagat G, Ghosh S
Nat Immunol
· 2026 Jun · PMID 42062562
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Celiac disease (CeD) is an autoimmune disorder triggered by dietary gluten. While HLA-DQ2/8-mediated presentation of gliadin peptides is required for disease, the mechanisms that underlie the loss of oral tolerance to gl...Celiac disease (CeD) is an autoimmune disorder triggered by dietary gluten. While HLA-DQ2/8-mediated presentation of gliadin peptides is required for disease, the mechanisms that underlie the loss of oral tolerance to gluten remain incompletely understood. Long-noncoding RNAs (lncRNAs) have been increasingly recognized as regulators of immune function, yet their role in oral tolerance has not been previously explored. Here, using a screen designed to identify lncRNAs responsive to T cell activation and enriched for CeD-associated GWAS variants, we identified lnc13 as a top candidate. In HLA-DQ8 transgenic mice lacking lnc13, unmanipulated gluten ingestion led to molecular signatures resembling human CeD and hallmark features of loss of oral tolerance to gluten: increased IFN-γ lymphocytes, IL-12 myeloid cells, cytotoxic intraepithelial immune cells and crypt hyperplasia in the small intestine. Mechanistically, lnc13 binds specific DNA regulatory regions and limits immune cell responsiveness to proinflammatory signals. In particular, lnc13 restrains IL-15-driven differentiation of CD8 natural killer-like lymphokine-activated killer cells (an IL-15-dependent pathway strongly implicated in CeD). These findings establish lnc13 as a critical noncoding modulator of oral gluten tolerance.
Pathogen-associated molecules can have both membrane-associated and intracellular receptors. Bacterial lipoproteins are recognized by Toll-like receptor 2, but it is unclear whether they can also be sensed by cytoplasmic...Pathogen-associated molecules can have both membrane-associated and intracellular receptors. Bacterial lipoproteins are recognized by Toll-like receptor 2, but it is unclear whether they can also be sensed by cytoplasmic receptors. Here we found that bacterial lipoproteins could be recognized in the cytoplasm of macrophages by cystathionine γ-lyase (CTH) and hydrolyzed into lipid chains containing sulfhydryl groups. The hydrolyzed lipid chains form molecules containing four acylated chains linked through disulfide bonds, which further cleave caspase-11 and activate the noncanonical inflammasome. Changing the redox environment in macrophages affects their recognition of bacterial lipoproteins. CTH-deficient primary and immortalized macrophages do not trigger activation of the noncanonical inflammasome in the presence of intracellular bacterial lipoproteins, while CTH-deficient mice exhibit attenuated immune responses to infection with Staphylococcus aureus and Listeria monocytogenes. Our findings elucidate the molecular mechanisms by which macrophages recognize intracellular bacterial lipoproteins, as well as the regulatory relationship between cellular redox levels and infection resistance.
Zhou X, Liu W, Hu J
… +19 more, Yao Q, Zhang F, Wu Q, Li L, Li J, Zhu L, Chen C, Zhang Q, Zhang R, Liu J, Shi C, Zhou H, Guo A, Wang J, Wang J, Hu Q, Li L, Jin T, Zeng Z
Liver metastases can resist T cell immunotherapies, indicating an adaptation of metastatic tumors toward reduced immunogenicity in the liver. Here we show that VSIG4, an immune checkpoint molecule predominantly expressed...Liver metastases can resist T cell immunotherapies, indicating an adaptation of metastatic tumors toward reduced immunogenicity in the liver. Here we show that VSIG4, an immune checkpoint molecule predominantly expressed by Kupffer cells, has an opposing function in determining the growth of liver metastases with distinct antigenicity by modulating cognate T cell antigen receptor signaling through an interaction with CD5. VSIG4-CD5 engagement impedes activation of low-affinity CD8 T cells while enhancing responses of high-affinity CD8 T cells by rescuing them from activation-induced cell death. This bidirectional regulation favors the outgrowth of poorly immunogenic metastatic tumor clones and fosters an immune landscape that is unfavorable to T cells as metastatic liver cancer progresses. We also show that blockade of VSIG4-CD5 interaction using a nanoantibody to VSIG4 sensitizes liver metastases to anti-PD-L1 therapy, achieving synergistic efficacy in mice. These findings provide mechanistic insights into cancer immunoediting during liver metastasis and a possible approach for treating immunologically cold tumors.
Wang Y, Afshari K, Haddadi NS
… +14 more, Lopes CS, Eng CL, Whiteman LM, Martinez N, Kyawe PP, Anufrieva KS, Wei K, Frieda K, Rosenbach M, Vleugels RA, Gallucci S, Harris JE, Rashighi M, Garber M
Nat Immunol
· 2026 Jun · PMID 42032302
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Photosensitivity is central to cutaneous lupus erythematosus and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial...Photosensitivity is central to cutaneous lupus erythematosus and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial transcriptomics, proteomics, UVB provocation and in vitro modeling, we identify MMP9CD14 myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce interferon-β (IFNβ) and colocalize with cytotoxic CD4 T cells at the dermal-epidermal junction. Keratinocytes activate fibroblasts in the superficial dermis, prompting them to release chemokines (CCL2, CCL19, CCL7, CCL8) that recruit MMP9CD14 cells. In vitro, type I interferon-primed keratinocytes exposed to UVB release cytokines activating dendritic cells, mirroring in vivo responses. UVB irradiation of non-lesional skin of patients with DM rapidly recruits these myeloid cells. In a clinical proof-of-concept study, anti-type I interferon treatment with anifrolumab prevented UVB-induced myeloid infiltration and reduced photosensitivity. Therefore, targeting MMP9CD14 cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions.
Zheng Y, Giri S, Zhang J
… +16 more, Chen Y, Yang A, Kale SL, Beeravolu H, Pannucci A, Marinov AD, Tilstra JS, He K, Creech A, Schwartz DM, Gottschalk RA, Bouladoux N, Belkaid Y, Cillo AR, Ray A, Poholek AC
Nat Immunol
· 2026 Jun · PMID 42032301
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Allergic asthma is driven by type 2 immune responses, including type 2 innate lymphoid cells (ILC2s). Although ILC2s are activated by the tissue alarmins interleukin (IL)-33 and IL-25, these signals do not intrinsically...Allergic asthma is driven by type 2 immune responses, including type 2 innate lymphoid cells (ILC2s). Although ILC2s are activated by the tissue alarmins interleukin (IL)-33 and IL-25, these signals do not intrinsically enforce type 2 identity and the mechanisms that maintain type 2 cytokine expression remain unclear. Here we show that allergen-induced IL-33 and IL-25 rapidly induce IL-9, which in turn upregulates the transcriptional repressor Blimp-1 in ILC2s. Blimp-1 sustains type 2 immunity by directly repressing type 1 inflammatory programs, including expression of interferon-γ and tumor necrosis factor. Deletion of Blimp-1 in ILC2s increased type 1 cytokine production and reduced IL-5 and IL-13 expression, eosinophil recruitment and mucus production in the lung. In contrast, IL-9 expression was enhanced in the absence of Blimp-1, leading to increased mast cell recruitment. Together, these findings identify Blimp-1 as a key regulator of ILC2 transcriptional fidelity that stabilizes type 2 inflammation while constraining divergent inflammatory programs during allergic responses.
Brain tumors are among the most lethal cancers, with limited success from emerging immunotherapies, largely due to the reshaping of the surrounding tumor microenvironment to promote tumor growth, invasion and immune evas...Brain tumors are among the most lethal cancers, with limited success from emerging immunotherapies, largely due to the reshaping of the surrounding tumor microenvironment to promote tumor growth, invasion and immune evasion. Astrocytes are abundant glial cells of the central nervous system (CNS) that can activate distinct molecular programs to support glioblastoma and brain metastases. Although astrocytes are central regulators of the immune response in the CNS, their role in shaping tumor immunity remains relatively underexplored. Emerging evidence indicates that reactive astrocytes are important drivers of local immunosuppression, which constitutes a major barrier to the development of efficacious immunotherapies for brain tumors. In this Review, we examine astrocyte reprogramming by tumor-derived signals, its effect on tumor immunity, and emerging strategies to modulate astrocyte responses and immunotherapy outcomes.
Bai Z, Lan T, Hong W
… +23 more, Que H, Zhu M, Xiao X, Wan D, Ai J, Huang S, Wang J, Hong Q, Liu Y, Xiao C, Zhao C, Wang X, Zhang X, Yang T, Xu H, Dai L, Powell CA, Richeldi L, Luo F, Dong H, Yuan Y, Pu Q, Wei X
Nat Immunol
· 2026 May · PMID 42010059
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Fibrosis is a severe pathological outcome of many chronic diseases, yet the therapeutic potential of targeting the altered major histocompatibility complex (MHC) class I immunopeptidome remains largely unexplored. Here w...Fibrosis is a severe pathological outcome of many chronic diseases, yet the therapeutic potential of targeting the altered major histocompatibility complex (MHC) class I immunopeptidome remains largely unexplored. Here we characterized the MHC class I immunopeptidomes from both fibrotic foci of human idiopathic pulmonary fibrosis lung explants and bleomycin-treated mice, identifying a diverse repertoire of fibrosis-associated peptides. Parallel profiling of bleomycin-induced pulmonary fibrosis in mice enabled the computational prioritization of therapeutic targets. In vivo, therapeutic vaccination with three candidate peptides (MAF, APBB2 and TNS3) effectively mitigated fibrosis progression in bleomycin-treated mice. Furthermore, leveraging its evolutionary conservation, we found that MAF elicited specific human cytotoxic T lymphocytes that lysed human idiopathic pulmonary fibrosis-derived myofibroblasts and M2-like macrophages. This study indicates that immunopeptidome profiling provides a robust platform for discovering translatable antifibrotic immunotherapies.