TH17 cells are an IL-17A-secreting subset of CD4+ T effector cells that defend against invading extracellular pathogens, maintaining immunity at skin and mucosal barriers under homeostatic conditions. In addition to IL-17A, they produce IL-17F, IL-21, and IL-22, recruiting other pro-inflammatory mediators to promote pathogen clearance. But when their activation goes awry, TH17 cells become key drivers of several autoimmune and chronic inflammatory diseases, including multiple sclerosis, psoriasis, and inflammatory bowel disease. While IL-17A/IL-17R neutralizing antibodies have found success in treating psoriasis, they have had limited success in inflammatory bowel disease, suggesting that targeting factors that broadly regulate TH17 cell function may be more effective. The lineage-defining transcription factor RORγt drives TH17 development, but a complex network of additional transcription factors works in concert to promote or inhibit TH17-mediated inflammation. The Solt laboratory previously identified that REV-ERBα acts as a negative regulator of the TH17 program in vitro and in vivo, and that REV-ERB-selective synthetic ligands mediated protection against TH17-driven diseases in mouse models of multiple sclerosis and ulcerative colitis. However, those ligands targeted both REV-ERBs or REV-ERBα alone, leaving the physiological function of REV-ERBβ in T cell effector responses largely unexplored.

To establish whether REV-ERBβ is required to limit TH17-mediated pro-inflammatory responses in vivo, the team used REV-ERBβ-deficient mice in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Immune phenotyping revealed no overt differences in thymocyte or T cell composition between wild-type and knockout animals under steady-state conditions. But when the researchers immunized both groups with myelin oligodendrocyte glycoprotein peptide (MOG35-55) and monitored disease daily, the knockout mice fared dramatically worse. Mean maximum disease score reached 3.57 in REV-ERBβ-deficient mice relative to 2.05 in wild-type littermates—a statistically significant difference—and the mean day of disease onset was also earlier, at 10.43 versus 11.62 days. Flow cytometric analysis of the central nervous system at the peak of disease revealed an increased frequency and number of CD4+ T cells infiltrating the CNS of knockout animals. The disease phenotype was not attributable to increased frequencies of CD4+CCR6+ cells or decreased frequencies of anti-inflammatory Foxp3+ T regulatory cells, as no differences were observed between genotypes. However, the frequency and number of CD4+RORγt+ cells were elevated in the knockout CNS, and while no statistically significant increase in IL-17A+ T cells was detected, there was a significant increase in the frequency and number of the IL-17A+IFNγ+ population—a double-positive subset whose acquisition of IFNγ has been linked to pathogenicity in several models of chronic disease, including EAE and multiple sclerosis.

Because the EAE model involved global deletion of REV-ERBβ, the excessive neuroinflammation could theoretically have stemmed from direct effects on microglia or other immune cell types rather than T cells themselves. To specifically assess T-cell-mediated effects, the researchers sorted naive CD4+ T cells from wild-type and REV-ERBβ-deficient mice and adoptively transferred them into Rag1-deficient recipients to track the development of colitis, another TH17-driven inflammatory disorder. Over a 12-week experiment, transfer of REV-ERBβ-deficient cells resulted in more severe weight loss and increased colon weight, a function of increased immune cell infiltration leading to exacerbated intestinal inflammation. Colon weight/length ratios—a measure that controls for measurement bias and reflects inflammation and edema—were also higher in mice receiving knockout cells, indicative of more intestinal inflammation. Quantitative real-time PCR of proximal colon tissue revealed significantly increased expression of the pro-inflammatory cytokine genes Il17a, Il17f, Il6, Tnf, and Ifng in mice receiving REV-ERBβ-deficient T cells compared to wild-type recipients. Expression of Il22 was also elevated but did not reach statistical significance, and Cxcl10—a gene activated downstream of IL-17 and IL-22 signaling—was increased, consistent with an overall heightened TH17 pro-inflammatory profile in vivo.

In a shorter-term experiment sacrificed at five to six weeks post-transfer, when T cells are just beginning to enter the colon, mice receiving REV-ERBβ-deficient T cells again showed increased colon weight and higher colon weight/length ratios. Flow cytometry revealed increased infiltration of total immune cells and increased frequency and number of CD3+CD4+ T cells in the mesenteric lymph nodes and colons of knockout-cell recipients, with no differences observed in the spleen. While mice receiving knockout cells did not show increased frequencies of CD4+RORγt+ or RORγt+IL-17A+ TH17 cells, there were increased absolute numbers of both populations in the colons. NanoString experiments on FACS-sorted T cells isolated from the colons confirmed increased expression of pro-inflammatory cytokines and chemokines, including Cxcl10, Ccr9, and Il22. Intriguingly, genes involved in oxidative stress and apoptosis—including Sod1, Bcl2, Casp3, Casp8, and Xiap—were decreased in REV-ERBβ-deficient T cells, suggesting the receptor may regulate apoptosis and cell survival in T cells within the colon. Expression of Il18rap was also downregulated; this receptor acts as a negative regulator of TH17 cell differentiation in the intestine, and its dysfunction is linked to intestinal diseases like Crohn’s disease, inflammatory bowel disease, and celiac disease.

To model REV-ERBβ-dependent T cell functions in vitro, the team tested the requirement for the receptor to limit pro-inflammatory cytokine expression in CD4+ T helper cells using congenic co-cultures. Naive CD4+ T cells from congenic CD45.1 wild-type and CD45.2 REV-ERBβ-deficient mice were differentiated under three different TH17 polarizing conditions: non-pathogenic (TGFβ plus IL-6), pathogenic 1 (TGFβ, IL-6, and IL-23), and pathogenic 2 (IL-6, IL-1β, and IL-23). Loss of REV-ERBβ decreased the ratio of knockout to wild-type cells in all three cultures, suggesting a cell-extrinsic effect on proliferation or survival. Despite the decreased frequency of knockout cells in culture, REV-ERBβ deficiency led to increased IL-17A production under non-pathogenic and pathogenic 1 conditions but not pathogenic 2 conditions, hinting at a potential requirement for TGFβ in the receptor’s regulatory effects. Carboxyfluorescein succinimidyl ester (CFSE) staining revealed no overt defects in proliferation, but a viability dye showed increased non-viable cells in knockout cultures, consistent with the decreased expression of Sod1, Bcl2, and Xiap seen in the NanoString data. These effects appear specific to TH17 cells, as loss of REV-ERBβ did not affect TH1 or inducible T regulatory cell differentiation.

To address whether REV-ERBβ affects TH17 cell function through cell-intrinsic or cell-extrinsic mechanisms in vivo, the researchers performed co-transfer experiments using the T cell transfer model of colitis, mixing equal numbers of congenic CD45.1+ wild-type and CD45.2+ REV-ERBβ-deficient naive CD4+ T cells before injection into Rag1-deficient recipients. After six weeks of expansion, there were decreased REV-ERBβ-deficient cells in the mesenteric lymph nodes and colon lamina propria, corroborating the in vitro data. Upregulation of the chemokine receptor CCR9 and the integrin α4β7 in mesenteric lymph nodes mediates lymphocyte homing to the intestinal lamina propria. While CCR9 expression was increased in REV-ERBβ-deficient T cells in the lymph nodes and colon, the knockout cells did not have an advantage homing to these sites. Despite this, REV-ERBβ-deficient T cells exhibited increased frequency of RORγt+ cells and RORγt+IL-22+ cells in the colons, along with increased frequency of IL-17A+IFNγ+ cells. These results demonstrate that REV-ERBβ is required to control T cell accumulation at inflammatory sites as well as temper downstream TH17 pro-inflammatory responses in a cell-intrinsic manner.

To gain a better understanding of the transcriptional programs controlled by each receptor, the team performed RNA-sequencing on TH17 cells collected at peak mRNA expression of each REV-ERB: time zero (naive) for REV-ERBβ and 24 hours post-activation for REV-ERBα. The results were striking. At both time points, there was very little overlap in transcriptional signatures between REV-ERBβ-deficient and REV-ERBα-deficient T cells. The genes that did overlap fell under metabolic pathways via KEGG analysis. At time zero, REV-ERBβ regulated a large number of pathways relative to REV-ERBα, including genes involved in the cell cycle (Ccnd2, Ccnd3, Ccnb1), whereas REV-ERBα regulated genes involved in circadian rhythm, consistent with its role as a core member of the circadian clock. REV-ERBβ also appeared to regulate genes involved in FoxO, JAK-STAT, and PI3K-Akt signaling pathways at time zero. In TH17 cells at 24 hours, REV-ERBβ regulated genes involved in Polycomb repressive complexes, Notch signaling, regulation of the actin cytoskeleton, and cellular senescence, whereas REV-ERBα regulated genes involved in CD4+ T cell differentiation, including TH1, TH2, and TH17 lineages. RT-qPCR further confirmed that post-activation, REV-ERBα was upregulated similar to RORγt, while REV-ERBβ was downregulated upon TH17 cell differentiation—a divergent expression pattern in contrast to what is observed in other tissues.

Because REV-ERBα’s repressive function is largely instilled by the co-repressor NCoR1, and homology led many to assume REV-ERBβ works similarly, the researchers probed whether this holds true. Mammalian two-hybrid assays in HEK293 cells demonstrated that the REV-ERBβ ligand binding domain can interact with NCoR1 in a dose-dependent manner. However, overlay of publicly available NCoR1 ChIP-seq peaks with differentially expressed genes from naive REV-ERBβ-deficient T cells revealed very little overlap—only 34 shared target genes. The overlapping genes were related more toward overall T cell activation and proliferation (Cd69, Ctse, Ccnd2, Ccnd3, Icos, Il7r, Ptpn22) than TH17 lineage specification. To determine whether REV-ERBβ represses transcription passively by displacing RORs from shared DNA binding sites or actively by recruiting co-repressor proteins, the team generated retroviral constructs encompassing the DNA binding domain alone (βDBD) or all but the DNA binding domain (βΔDBD), along with a heme binding mutation (βHBM, H565F) that reduces heme binding affinity more than 10,000-fold. When overexpressed in TH17 cells, the truncation and deletion constructs were unable to repress Il17a relative to wild-type REV-ERBβ, indicating that active repression requires both DNA binding and cofactor recruitment via the ligand binding domain. Remarkably, the heme binding mutation did not relieve repression at IL-17A, and RNA-sequencing showed it had little effect on transcription, relieving repression of only about 10–15% of wild-type target genes. These data suggest REV-ERBβ functions in a largely heme-independent manner in TH17 cells—a non-canonical signaling mechanism that contrasts sharply with REV-ERBα, whose heme-dependent NCoR1 interaction recruits the histone deacetylase HDAC3 to repress transcription at Il17a.

The findings carry significant therapeutic implications. Several small molecules targeting both REV-ERBα and REV-ERBβ have been developed as alternatives to RORγt modulators, and the Solt laboratory recently developed a ligand selective for REV-ERBα over REV-ERBβ. But the current data suggest that targeting both factors would be ideal to better encompass inhibition of the TH17 program in vivo—both during the initial development of TH17 cells, when REV-ERBβ is more highly expressed, and later post-activation, when REV-ERBα dominates. By this logic, ligands that target both REV-ERBs would have a greater repressive effect than a ligand targeting only a single receptor subtype. The work also raises a compelling paradox: in vivo, REV-ERBβ-deficient TH17 cells accumulate at lesion sites, yet in vitro they exhibit increased cell death. The researchers suggest that in vivo, these cells may reside in a supportive ecosystem, interacting with stromal cells and antigen-presenting cells that provide survival signals absent in culture. Future experiments testing competition, cell death versus proliferation, and accumulation under both conditions would tease out this contradiction. The team acknowledges limitations, including the use of retroviral overexpression rather than endogenous gene editing, the lack of ChIP-grade REV-ERBβ antibodies to map binding sites, and the inability to completely rule out REV-ERBβ’s independence from REV-ERBα using single knockout systems. Nevertheless, the study establishes for the first time that individuality exists between the two REV-ERB receptors in TH17 cells, suggesting they complement each other in a spatiotemporal network rather than overlapping patterns—a discovery that reshapes how scientists think about circadian nuclear receptors in immunity and opens new avenues for treating TH17-driven autoimmune disease.

Subject of Research: Non-redundant negative regulation of TH17-mediated inflammation by the nuclear receptor REV-ERBβ

Article Title: Negative regulation of T H 17-mediated inflammation by the nuclear receptor REV-ERBβ

Article References: Campbell, S., Mosure, S. A., Amir, M., Chuck, J., Lu, Q., & Solt, L. A. (2026). Negative regulation of TH17-mediated inflammation by the nuclear receptor REV-ERBβ. iScience, 29(11), Article 117577. https://doi.org/10.1016/j.isci.2026.117577

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117577

Keywords: REV-ERBβ, REV-ERBα, TH17 cells, autoimmunity, nuclear receptor, IL-17A, EAE, colitis, NCoR1, heme, circadian clock, inflammation

The study, published in Frontiers in Allergy, tackled a stubborn translational problem. The inflammatory state of the deep nasal mucosa is known to shape whether the delicate olfactory neuroepithelium can regenerate, but reaching that state has traditionally required invasive tissue biopsies, which are impractical for routine pre-operative screening or repeated outpatient monitoring. Nasal secretions, which directly bathe the olfactory cleft, offer an ideal biological window, yet the precise mapping between deep-tissue inflammation and superficial secretory chemistry has remained largely unknown.

To bridge that gap, the team led by Hangtian Zhang, Linlu Wang, Tong Lu, and Yilin Hou, under the senior authorship of Jian Li, Weiping Wen, and Hua Zhong, designed a tissue-to-secretion dual-cohort strategy. In a discovery cohort of 67 patients, a Random Forest machine learning algorithm screened deep-tissue proteomes quantified with a Luminex multiplex platform, ranking candidates by their contribution to predictive accuracy. An independent Random Forest model then evaluated non-invasive nasal secretions, profiled with high-sensitivity Olink proximity extension assay technology, in a validation cohort of 62 patients. The two cohorts were well matched in age, sex, CT-based disease severity, blood inflammatory counts, and comorbid asthma and allergic rhinitis, ensuring that the cross-compartment molecular mapping was not confounded by clinical disparities.

The machine learning screen revealed a compelling pathophysiological landscape. Rather than a homogenous Type 2 inflammatory burden, the canonical signature long blamed for polyp growth and olfactory damage, the top 20 tissue candidates included potent Type 1 and Type 3 mediators such as tumor necrosis factor-alpha and interleukin-17, alongside the macrophage chemoattractant MCP-1 and classical Type 2 cytokines like IL-13 and IL-5. This mixed-endotype picture, in which neutrophilic inflammation coexists with Type 2 signals, is increasingly recognized as a driver of severe polypoid remodeling, particularly in Asian cohorts.

The critical test was whether these deep-tissue signals could survive translation to the secretory compartment. Eight top-tier tissue candidates, defined by a Mean Decrease Gini index above 1.0, were cross-referenced with the Olink Target 96 Inflammation panel. Five, MCP-1, TNF-alpha, IL-13, IL-5, and IL-17A, were successfully matched and quantified in nasal secretions. The results were striking: the canonical Type 2 cytokines IL-5 and IL-13, and even the dominant tissue chemoattractant MCP-1, lost all predictive significance in secretions. Only the non-Type 2 axes retained clinical relevance, with secretory IL-17A demonstrating the strongest continuous dose-response relationship with absolute olfactory improvement, a Spearman correlation of 0.334 with a P value of 0.0003, roughly two orders of magnitude stronger than the next best candidate.

That discrepancy between tissue and secretion is itself a scientific finding. In bulk tissue homogenates, IL-17’s standalone linear predictive capacity was notably weak, likely because its independent prognostic signature is masked by the overwhelming Type 2 background and complex stromal interactions within the polypoid bed. The secretory compartment, by contrast, appears to act as a biological filter. The team postulates that high concentrations of IL-17A in nasal secretions serve as a direct, functional readout of epithelial barrier collapse and tight junction disruption, isolating terminal pathogenic signals of neuroepithelial leakage from the convoluted deep-tissue inflammatory background.

Multivariate logistic regression confirmed that secretory IL-17A was an independent protective factor for olfactory recovery, with an odds ratio of 1.408 per unit increase, after adjusting for baseline disease severity. Higher pre-operative visual analog scale scores, by contrast, independently decreased the likelihood of achieving a clinically meaningful recovery threshold, defined as an absolute improvement of at least 3 points or a final 6-month score of 3 or less. The counterintuitive protective role of IL-17A, a cytokine conventionally recognized for disrupting epithelial tight junctions and driving neutrophilic infiltration, suggests a paradigm shift. Within an extreme, recalcitrant CRSwNP cohort, the presence of an IL-17A-associated mixed inflammatory endotype may reflect a higher degree of neuroepithelial plasticity and post-operative reversibility than a homogenous, end-stage Type 2 milieu, which is thought to lead to terminal, irreversible neural degradation.

Translating these insights into point-of-care practice, the team constructed a clinical-molecular nomogram integrating baseline VAS and secretory IL-17A. The joint model achieved an optimism-corrected area under the receiver operating characteristic curve of 0.793 after 1,000 bootstrap resamples, with adequate calibration and, as demonstrated by decision curve analysis, substantially superior net clinical benefit across a broad spectrum of threshold probabilities compared to treat-all or treat-none default strategies or a model relying solely on baseline symptom severity. Classical severity markers, including peripheral blood eosinophil percentage, Lund-Mackay CT scores, and olfactory cleft scores, did not exhibit independent predictive significance in the current cohort, underscoring the parsimony of the final model.

The authors acknowledge limitations, including the absence of an independent external validation cohort and the need for objective psychophysical testing such as Sniffin’ Sticks in future multicenter studies. Yet the framework offers rhinologists a highly actionable tool for personalized pre-operative counseling, empowering clinicians to preemptively identify refractory patients who might benefit from intensified perioperative medical adjuncts, such as targeted biologics or systemic corticosteroids, rather than relying solely on surgical intervention. By filtering out the profound Type 2 background noise predominant in severe CRSwNP, the study identifies secretory IL-17A as a specific, non-invasive indicator of mucosal plasticity and olfactory reversibility, marking a significant step toward precision medicine in one of otolaryngology’s most recalcitrant symptoms.

Subject of Research: Non-invasive prediction of olfactory recovery after sinus surgery using secretory IL-17A in chronic rhinosinusitis with nasal polyps

Article Title: Non-invasive prediction of olfactory recovery in severe CRSwNP: a cross-compartment translational nomogram based on secretory IL-17A

Article References: Zhang, H., Wang, L., Lu, T., Hou, Y., Wei, Y., Huang, W., Liu, S., Huang, Y., Xu, Z., Li, J., Wen, W., & Zhong, H. (2026). Non-invasive prediction of olfactory recovery in severe CRSwNP: a cross-compartment translational nomogram based on secretory IL-17A. Frontiers in Allergy, 7, Article 1978136. https://doi.org/10.3389/falgy.2026.1978136

Image Credits: AI Generated

DOI: 10.3389/falgy.2026.1978136

Keywords: olfactory recovery, CRSwNP, IL-17A, nasal secretions, biomarker, machine learning, nomogram, Type 2 inflammation, sinus surgery, liquid biopsy, Non-invasive, prediction

The starting point for the investigation was a careful characterization of what actually goes wrong in diarrheic calves. Compared with healthy animals, calves suffering from neonatal diarrhea showed pronounced gut microbial dysbiosis, meaning the composition of their intestinal bacterial communities had shifted away from a balanced state, together with measurable metabolic perturbation and clear signs of inflammatory activation. These observations established the pathological backdrop against which any candidate intervention would need to be evaluated, and they highlighted the possibility that restoring a healthy microbial community might restore a healthy gut.

To test that possibility directly, the researchers turned to fecal microbiota transplantation, or FMT, a technique that transfers the entire gut microbial community from healthy donor animals into sick recipients. When fecal material from healthy calves was transplanted into diarrheic calves, the treatment alleviated diarrhea. Crucially, the recovery was accompanied by enrichment of B. pseudocatenulatum in the recipients’ intestines and by an increase in fecal acetate, one of the major short-chain fatty acids produced by bacterial fermentation in the gut. This correlation gave the team two concrete leads: a specific bacterial species and a specific bacterial metabolite that moved in the same direction as clinical improvement.

The next step was to determine whether the bacterium itself could generate the acetate signal. In laboratory cultures, live B. pseudocatenulatum increased acetate production, confirming that this species is a genuine acetate producer rather than a passive correlate of health. This matters because it establishes a plausible causal route from bacterium to metabolite to host physiology, rather than a mere association, and it focused the team’s attention on acetate as the likely functional mediator of the probiotic effect.

To dissect that mechanism under controlled conditions, the investigators used complementary murine inflammatory models, in which mice were subjected to inflammatory challenges that mimic the intestinal damage seen in diarrheic calves. Treatment with live B. pseudocatenulatum or with acetate itself alleviated intestinal injury and the associated inflammatory phenotypes in these animals. By contrast, the protective effect was attenuated in mice given heat-killed B. pseudocatenulatum, a result with important mechanistic implications: a dead bacterium cannot ferment substrates into metabolites, so the loss of protection when the organism is killed points squarely to an activity of living bacteria, most plausibly their metabolic output, as the source of the benefit rather than a structural component of the bacterial cell.

Perhaps the most technically interesting part of the study concerns the immune pathway that the bacterium and its metabolite engage. The team found that the protective effects were accompanied by attenuation of pathogen-induced Th17/IL-17A-related responses. The Th17 lineage is a subset of CD4-positive T helper cells defined in large part by their production of the cytokine interleukin-17A, a potent inflammatory messenger that recruits neutrophils and drives antimicrobial defense but also fuels tissue damage when overactivated. Importantly, the authors emphasize that the effect was not a broad suppression of basal Th17 activation; the bacterium and acetate selectively dampened the exaggerated, pathogen-driven arm of this response while leaving ordinary Th17 activity largely intact. That selectivity is a desirable property for any anti-inflammatory therapy, because wholesale immune suppression would leave young animals vulnerable to infection.

The team then probed the receptor side of the acetate signal. Acetate can signal to host cells through free fatty acid receptor 2, or FFAR2, a G-protein-coupled receptor expressed on immune and epithelial cells that functions as a sensor for short-chain fatty acids. When the researchers used pharmacological blockade of FFAR2, the protective effect of live B. pseudocatenulatum was attenuated, supporting the involvement of acetate-associated receptor signaling in the probiotic benefit. Complementary experiments reported in the supplementary material of the study also showed that Brodalumab, an antibody that blocks the signaling of IL-17 family cytokines, counteracted the protective effect of acetate in a mouse colitis model driven by Salmonella Typhimurium, further tying the pathway together at the cytokine level.

The murine models tested a range of inflammatory insults beyond a single pathogen, and the results were consistent across them. B. pseudocatenulatum and acetate, supplied as sodium acetate, protected against intestinal injury in mice challenged with Escherichia coli and in models of Salmonella Typhimurium-induced inflammation and DSS-induced colonic inflammation. In the E. coli-challenged mice, the bacterium restored intestinal morphology, promoted acetate production, remodeled gut microbiota composition, and modulated T-cell subsets and inflammatory factors, along with the expression of genes involved in immune responses and metabolism in the intestinal epithelium. Supplementary analyses in calves showed that sodium acetate supplementation influenced serum biochemical indicators, extending the metabolite-level evidence to the target species itself.

Taken together, the study lays out a coherent mechanistic framework: dysbiosis in diarrheic calves depletes protective, acetate-producing taxa such as B. pseudocatenulatum; restoring those taxa, whether by whole-community FMT or by targeted supplementation, replenishes the acetate pool; acetate then acts through FFAR2 to restrain the pathogen-induced surge of the Th17/IL-17A axis, thereby reducing intestinal inflammation and the diarrhea it produces. The authors present this as one component of the bacterium’s protective effect rather than the whole story, a measured framing that reflects the inherent complexity of gut ecosystems and the many metabolites and immune circuits that operate in parallel.

The practical implications are considerable. Neonatal calf diarrhea imposes substantial economic losses on dairy and beef operations worldwide, and current management relies heavily on antibiotics, rehydration therapy, and husbandry measures, approaches that face growing pressure from antimicrobial resistance concerns. A defined probiotic species with an understood mechanism of action, acting through a well-characterized metabolite and receptor pathway, offers a rational and mechanistically grounded alternative or complement to existing treatments. More broadly, the microbiota–metabolite–immune regulatory framework established in this work provides a template that researchers in animal science and human gastroenterology alike can use to dissect how specific commensal organisms and their metabolic products tune inflammatory responses, and it underscores how much therapeutic insight can be extracted from tracing a single bacterial species and its small-molecule signal from the feces of a sick calf all the way to a cytokine axis in the gut wall.

Subject of Research: Acetate-mediated immune modulation by Bifidobacterium pseudocatenulatum in neonatal calf diarrhea

Article Title: Bifidobacterium pseudocatenulatum alleviates neonatal calf diarrhea via acetate-associated attenuation of pathogen-induced Th17/IL-17A inflammatory responses

Article References: Hu, M., Du, W., Li, W., Du, Y., Si, W., Hou, J., Gao, Y., Yang, L., Sun, H., Liu, H., Yu, Z., Guan, L., & Xu, Q. (2026). Bifidobacterium pseudocatenulatum alleviates neonatal calf diarrhea via acetate-associated attenuation of pathogen-induced Th17/IL-17A inflammatory responses. Microbiome. https://doi.org/10.1186/s40168-026-02524-4

Image Credits: AI Generated

DOI: 10.1186/s40168-026-02524-4

Keywords: Bifidobacterium pseudocatenulatum, neonatal calf diarrhea, gut microbiome, acetate, short-chain fatty acids, Th17 cells, IL-17A, FFAR2, intestinal inflammation, fecal microbiota transplantation, probiotics, livestock health

Non-tuberculous mycobacteria, often abbreviated NTM, are environmental organisms that increasingly cause chronic and debilitating lung disease worldwide. Among them, Mycobacterium abscessus stands out as particularly menacing. It is naturally resistant to many standard antibiotics, it can form ropelike cords that shield it from engulfment by immune cells, and it thrives in patients with pre-existing lung damage such as bronchiectasis, cystic fibrosis, or pulmonary fibrosis. Treatment regimens typically stretch for many months, involve multiple toxic drugs, and frequently fail to eradicate the infection. Against this grim clinical backdrop, the question of how the immune system naturally fights M. abscessus has remained surprisingly underexplored, particularly with respect to γδ T cells, an unconventional lymphocyte population whose role in NTM infection had never been systematically characterized.

γδ T cells differ from the conventional αβ T cells that dominate textbook immunology. Rather than recognizing peptide fragments presented by major histocompatibility molecules, they respond rapidly to a wide range of stress signals and microbial products, earning them a reputation as a bridge between innate and adaptive immunity. A major subset of these cells produces interleukin-17A, a powerful inflammatory cytokine best known for recruiting neutrophils and shaping defenses at body surfaces. To determine whether these cells matter in M. abscessus infection, the researchers built a mouse model of pulmonary infection and mapped the immune landscape of lung tissue over the early days of disease using single-cell RNA sequencing, a technique that captures the gene expression profile of thousands of individual cells simultaneously.

The single-cell atlas revealed a striking pattern. As infection took hold, γδ T cells accumulated in the lung and expanded a population that expressed high levels of IL-17A. When the team removed γδ T cells entirely, using mice genetically engineered to lack them, the consequences were dramatic: bacteria persisted at far higher levels in the lungs and spleens, and lung inflammation worsened. Conversely, when γδ T cells were depleted in animals that had already cleared a first infection and were then re-challenged, the protective advantage of prior exposure evaporated. These experiments established γδ T cells as indispensable players in the early defense against M. abscessus, a finding that had not been demonstrated before for any non-tuberculous mycobacterial pathogen.

Delving deeper, the investigators identified IL-17A itself as the linchpin of this protective response. Mice unable to produce IL-17A lost much of their capacity to control the infection, and importantly, the defect traced back to the γδ T cells themselves. Without IL-17A signaling, the cells became less adept at recognizing the bacterium and lost much of their cytotoxic firepower. In an elegant series of transfer experiments, IL-17A-deficient γδ T cells failed to protect infected animals, whereas their normal counterparts succeeded. This revealed something unusual: IL-17A was not merely acting as a broadcast signal to other immune players but was required within the γδ T cells themselves, a cell-intrinsic requirement that underscores how tightly the cytokine and its producer are wired together during this infection.

The mechanism by which these cells actually kill the bacterium proved to be equally instructive. M. abscessus is an extracellular pathogen during key phases of infection, residing outside host cells in the airways and tissue spaces. The researchers found that IL-17A-positive γδ T cells eliminated extracellular bacteria through a granzyme B-dependent cytotoxic pathway. Granzyme B is a serine protease classically associated with the destruction of virus-infected or malignant cells, delivered through pore-forming perforin or other release mechanisms. Its deployment against free-living bacteria adds a new dimension to the antimicrobial portfolio of γδ T cells and explains how a lymphocyte population usually discussed in the context of autoimmunity and inflammation can act as a direct bactericidal weapon.

How, then, does the immune system know to mobilize these cells in the first place? The answer lies in a cascade that begins with Toll-like receptor 2, a pattern-recognition receptor on macrophages that detects components of the bacterial cell wall. When M. abscessus engaged TLR2 on lung macrophages, the macrophages responded by secreting two cytokines, interleukin-1β and interleukin-23. This cytokine pair is a well-known stimulus for IL-17 production in T cells, and in this context it drove both the expansion and the activation of the IL-17A-positive γδ T cell population. Blocking either IL-1β or IL-23 in infected mice diminished the γδ T cell response and impaired bacterial control, mapping out a complete signaling axis that runs from bacterial recognition through macrophage activation to lymphocyte mobilization and, ultimately, bacterial killing.

Perhaps the most clinically resonant aspect of the study concerns patients whose immunity depends on interferon-gamma, the canonical cytokine for defense against mycobacteria. A subset of individuals, particularly in Southeast Asia, develops autoantibodies that neutralize their own interferon-gamma, leaving them exquisitely vulnerable to disseminated NTM infections. Using single-cell RNA sequencing of peripheral blood cells from NTM patients, the researchers found evidence that anti-interferon-gamma autoantibodies compromise γδ T cell function in humans, mirroring what they observed in mice lacking the interferon-gamma receptor. Crucially, in mice engineered without functional interferon-gamma signaling, IL-17A-positive γδ T cells still conferred protection, and the same held true in a model combining M. abscessus infection with bleomycin-induced pulmonary fibrosis. In other words, this arm of immunity operates independently of the interferon-gamma axis and remains effective even in scarred, damaged lungs.

The implications for therapy are considerable. Current treatment of NTM disease relies almost entirely on antibiotics that the pathogen is adept at resisting, and there are no licensed immunotherapies that bolster host defenses. If the pathways defined in this study can be harnessed in patients, whether by stimulating IL-1β and IL-23 signaling, expanding protective γδ T cell populations, or delivering IL-17A-driven cytotoxic activity directly, clinicians could gain a means of strengthening the lung’s own antimicrobial machinery. Such approaches would be especially valuable for the growing population of patients with anti-interferon-gamma autoantibodies or structural lung disease, for whom conventional regimens offer diminishing returns. The researchers caution that translating mouse findings to the clinic will require careful work, particularly because IL-17A is also implicated in inflammatory conditions such as psoriasis and could carry safety risks if induced systemically. Nevertheless, the identification of a concrete, mechanistically defined cell type that can clear M. abscessus marks a genuine advance. It transforms γδ T cells from immunological bystanders into a promising therapeutic target, and it reframes the fight against antibiotic-resistant mycobacteria as a battle that the immune system, with the right encouragement, may be able to win on its own terms.

Subject of Research: The role of IL-17A-producing γδ T cells in controlling pulmonary Mycobacterium abscessus infection in mice.

Article Title: IL-17A-producing γδ T cells control pulmonary Mycobacterium abscessus infection in mice

Article References: Hu, X., Lin, S., Meng, W., Liu, H., Qin, Z., Wu, Z., Wan, Y., Ma, S., Yang, X., Yin, Z., Chu, Y., Zhang, W., Shao, L., & Lin, Y. (2026). IL-17A-producing γδ T cells control pulmonary Mycobacterium abscessus infection in mice. Nature Microbiology. https://doi.org/10.1038/s41564-026-02466-5

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02466-5

Keywords: Mycobacterium abscessus, non-tuberculous mycobacteria, γδ T cells, IL-17A, interferon-gamma, granzyme B, TLR2, IL-1β, IL-23, pulmonary infection, immunology, antibiotic resistance