Discovery immunology最新文献

{"title":"The cognitive mechanism: safeguarding the future of immunological discovery in the GenAI era.","authors":"Nigel J Francis, David P Smith","doi":"10.1093/discim/kyag016","DOIUrl":"https://doi.org/10.1093/discim/kyag016","url":null,"abstract":"<p><p>Scientific discovery is built on the rigorous interrogation of the unknown. In immunology, exploring novel mechanisms requires researchers to identify what is unknown, reconcile contradictory data through original thinking, and integrate disparate ideas to generate testable hypotheses. Undertaking this process is how students construct their own knowledge and experiences. However, the rapid integration of Generative AI (GenAI) into higher education risks short-circuiting this cognitive process. Time-poor students, facing mounting pressure, increasingly use GenAI to offload thinking onto algorithms, sidestepping the very struggle that develops scientific curiosity and critical judgment. This opinion piece argues that without adequate guardrails, we risk training scientists who simulate competence but lack the capacity for genuine discovery. Taught programmes must be designed with academic integrity in mind and embrace assessment innovations. Rather than engaging in a futile arms race to detect outputs, educators must shift assessment from traditional final products, such as essays and lab reports, to validating the research process itself and assessing directly the capacities that future graduates will need. By assessing research trails, interpretation of raw data, and the thinking process behind GenAI use (identifying gaps, bias, and hallucinations) through viva-style interactions, we ensure that student cognitive effort remains the driver of the work. Ultimately, the quality of future immunological research depends on the integrity of our current assessment methods.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag016"},"PeriodicalIF":0.0,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fixation matters: duration in fixative prior to immunofluorescent analysis directly impacts macrophage visualization in epithelial tissues.","authors":"Lizi M Hegarty, Erin Watson, Calum C Bain, Elaine Emmerson","doi":"10.1093/discim/kyag015","DOIUrl":"10.1093/discim/kyag015","url":null,"abstract":"<p><strong>Introduction: </strong>Macrophages are now recognized as key players in a range of tissues and biological processes, responding to injury and infection, and facilitating development and regeneration. As the importance of macrophage crosstalk within these processes has been revealed, so too has the significance of studying the spatial positioning of macrophages within the tissue of interest. As such, immunofluorescent microscopy-based analysis is becoming an increasingly attractive technique for immunology research. While tissue fixation preserves the tissue architecture and immobilizes target antigens, prolonged fixation can negatively impact protein recognition.</p><p><strong>Methods: </strong>We compared three different durations of tissue fixation and the expression of key macrophage and structural cell markers in the submandibular gland, pancreas, kidney, and skin by immunofluorescent imaging.</p><p><strong>Results: </strong>We report that prolonged exposure to a paraformaldehyde-based fixative profoundly impacts detection of cell surface markers that define macrophage subsets in the mouse submandibular gland, in contrast to epithelial cell markers, which appear more robust. We find that this is not exclusive to the salivary gland, and similar effects are seen in the pancreas and kidney. Importantly, a short duration of fixation allowed the detection of macrophage subsets in both mouse and human tissue without compromising the detection of other markers.</p><p><strong>Conclusion: </strong>Adoption of a short fixation approach enables accurate detection of a wide range of cell types in tissues, and facilitates exploration of spatial positioning and cell proximity by immunofluorescent microscopy analysis.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag015"},"PeriodicalIF":0.0,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct lipid transport proteins are regulated by innate immune stimuli.","authors":"Lydia P Tsamouri, Najd M Aljadeed, Antoni Olona, Paras K Anand","doi":"10.1093/discim/kyag014","DOIUrl":"10.1093/discim/kyag014","url":null,"abstract":"<p><strong>Introduction: </strong>Lipid transport plays a critical role in the distribution of lipids across subcellular compartments. This is pivotal during infection and other stress stimuli that increase metabolic demands. While lipid biosynthesis is regulated by immune stimuli, whether immune signalling also influences lipid transport mechanisms remains unexplored.</p><p><strong>Methods: </strong>We examined the effect of TLR and IFN-γ signalling on the gene expression of lipid transport proteins in human monocytic THP-1 cell line and compared these responses with those in primary bone marrow-derived mouse macrophages.</p><p><strong>Results: </strong>Our data demonstrate that TLR4 signalling selectively modulates the expression of oxysterol-binding protein-related proteins (ORPs), a key family of proteins that transport lipids between organelles. Remarkably, TLR4 activation led to the downregulation of several ORP family members in human THP-1-derived macrophages. However, this response was less profound in mouse macrophages. In contrast, the expression of steroidogenic acute regulatory domain (STARD) proteins, many of which transport lipids between mitochondria and other compartments, exhibited no statistical difference. Moreover, IFN-γ, a cytokine that plays a key role in the immune response, did not considerably impact human ORP or STARD expression levels, either alone or in combination with LPS.</p><p><strong>Conclusion: </strong>Together, these results reveal that TLR signalling exerts selective and critical control over lipid trafficking pathways with important biological differences. These findings provide new insights into the crosstalk between immune signalling and lipid metabolism, which may offer novel targets to treat diseases characterized by dysregulated lipid pathways.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag014"},"PeriodicalIF":0.0,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An autoinflammatory RIG-I variant causing Singleton-Merten syndrome associates with small non-coding Y-RNAs.","authors":"Benjamin J Thompson, Christ C P Leemans, Dennis Gravekamp, Amarise-Jourmaine M H Silie, Jorn E Stok, Jasper W de Wolf, Erik B van den Akker, Frank J T Staal, Hailiang Mei, Annemarthe G van der Veen","doi":"10.1093/discim/kyag013","DOIUrl":"10.1093/discim/kyag013","url":null,"abstract":"<p><strong>Introduction: </strong>The RNA sensor retinoic acid-inducible gene I (RIG-I) performs a critical role in surveying the cytoplasm for the presence of viral nucleic acids and initiating the downstream anti-viral type I interferon pathway. Through recognition of specific features, such as the presence of a 5' tri/diphosphate motif or highly structured base-paired regions, RIG-I effectively differentiates between RNA of viral- and self-origin. In Singleton-Merten syndrome (SMS), gain-of-function variants in RIG-I lead to a breakdown in this surveillance system and results in aberrant sensing of self-RNAs and deleterious upregulation of type I interferons. The identity of the self-RNAs binding to gain-of-function RIG-I mutants has remained elusive and their elucidation would provide a greater understanding of the aetiology of SMS.</p><p><strong>Methods: </strong>Here we used an infrared individual-nucleotide resolution UV-crosslinking and immunoprecipitation (irCLIP) approach to determine the RNA profile bound to a previously characterized ATPase-deficient SMS variant, RIG-I^C268F.</p><p><strong>Results: </strong>irCLIP identified a broad array of self-RNAs, primarily those transcribed by RNA polymerase III, that were bound to RIG-I. Subsequent native RNA immunoprecipitation confirmed a prominent and specific interaction between RIG-I^C268F and Y-RNAs, a family of four structurally similar non-coding RNAs.</p><p><strong>Conclusion: </strong>Manipulation of Y-RNAs alone by targeting either Y-RNA transcripts or Y-RNA stabilizing proteins was insufficient to negate RIG-I induced interferon responses, hinting at a broader profile of RNA polymerase III-derived RNAs being influential in driving the sterile activation of gain-of-function RIG-I variants.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag013"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendritic-cell diversity in equine blood revealed by single-cell transcriptomics.","authors":"Ambre Baillou, Marius Botos, Simone Oberhaensli, Iva Cvitas, Sigridur Jonsdottir, Anja Ziegler, Francisco Brito, Artur Summerfield, Eliane Marti, Stephanie C Talker","doi":"10.1093/discim/kyag012","DOIUrl":"10.1093/discim/kyag012","url":null,"abstract":"<p><strong>Introduction: </strong>Detailed classification of equine dendritic cells (DC) is necessary to address various research questions, such as the role of DC subsets in immune-mediated diseases of horses.</p><p><strong>Methods: </strong>We applied single-cell RNA sequencing (scRNA-seq) on DC enriched from the blood of two horses.</p><p><strong>Results: </strong>All main DC subsets were detected by key gene expression, including conventional DC type 1 (cDC1; <i>XCR1</i>) and type 2 (cDC2; <i>FCER1A</i>, <i>CD1E</i>), as well as plasmacytoid DC (pDC; <i>TCF4</i>). In addition, we detected a small cluster of hematopoietic progenitors, as well as transitional DC (tDC; <i>FCER1A</i>, <i>TCF4</i>) and putative DC type 3 (DC3; <i>FLT3</i>, <i>CD163</i>). Our data confirms the previously reported phenotype of equine pDC (Flt3⁺MHC-II^lowCADM1^lowCD172a^int), cDC1 (Flt3⁺MHC-II^highCADM1^highCD172a^low-int), and cDC2 (Flt3⁺MHC-II^highCADM1^intCD172a^high), while also highlighting considerable CD14 expression for cDC2. Two subclusters of equine cDC2 were found to be enriched in <i>FCER1A</i> or <i>CX3CR1</i> transcripts (cDC2.1 and cDC2.2, respectively), with suggested enhanced extravasation and T-cell stimulatory capacities of the latter. Conservation of DC subsets across species (horse, pig, human, mouse) was illustrated by enrichment analyses with subset-specific gene signatures and by cross-species data integration with publicly available scRNA-seq datasets.</p><p><strong>Conclusion: </strong>Our atlas of equine blood DC is a valuable resource for comparative analyses, and it forms the foundation for understanding the involvement of distinct DC subsets in infections and immune-mediated pathologies.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag012"},"PeriodicalIF":0.0,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies.","authors":"Gabriela Nieva, Florencia Vassallu, Amaicha Depino, Vanina Netti, Lionel Muller Igaz","doi":"10.1093/discim/kyag011","DOIUrl":"10.1093/discim/kyag011","url":null,"abstract":"<p><strong>Introduction: </strong>Aggregation and cytoplasmic mislocalization of TDP-43 are key features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuroinflammatory processes mediated by glial cells play crucial roles in the pathophysiology of these and other diseases, defined as TDP-43 proteinopathies. Here, we characterized region-specific glial activation in two conditional mouse models: hTDP-43-WT (overexpressing nuclear wild-type human TDP-43) and hTDP-43-ΔNLS (expressing cytoplasmic TDP-43 with altered nuclear localization signal) following 1 month of transgene expression.</p><p><strong>Methods and results: </strong>Immunofluorescence analysis revealed distinct patterns of microglial activation across brain regions. hTDP-43-WT mice exhibited significant microgliosis in motor (MC) and somatosensory (SSC) cortices and hippocampal dentate gyrus (DG) with pronounced morphological alterations (i.e. increased soma size). Sholl analysis demonstrated reduced branching length and complexity in MC, SSC, and hippocampal subfields. hTDP-43-ΔNLS mice displayed more pronounced microglial activation in hippocampal regions (CA1, DG) compared to cortical areas, with significant increases in microglial density. Additionally, we observed region-specific cortical astrocytosis in both models, suggesting coordinated glial reactivity. hTDP-43-ΔNLS mice showed decreased polarization of astrocytic water channel Aquaporin-4 (AQP4) around vascular structures in SSC and hippocampal CA1/DG. The changes in AQP4 localization, which is critical for glymphatic function, support the hypothesis that this waste clearance system for the brain is altered in TDP-43 proteinopathies.</p><p><strong>Conclusion: </strong>These findings demonstrate that these different animal models of ALS/FTD induce distinct neuroinflammatory signatures, potentially contributing to the region-specific vulnerability observed in these diseases. Our data provide insights into early glial-mediated pathogenic mechanisms that could guide targeted therapeutic strategies for TDP-43 proteinopathies.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag011"},"PeriodicalIF":0.0,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148392691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using peptide-exchange systems to interrogate peptide-specific KIR binding to HLA Class I.","authors":"Tanusya M Murali, Beining Li, Emery Hoos, Lucy Collinson, Eric O Long, Omer Dushek, Tim Elliott, Malcolm J W Sim","doi":"10.1093/discim/kyag010","DOIUrl":"10.1093/discim/kyag010","url":null,"abstract":"<p><strong>Introduction: </strong>The killer-cell immunoglobulin-like receptors (KIR) are a family of activating and inhibitory Class I human leukocyte antigen (HLA-I) binding receptors expressed on natural killer (NK) cells and subsets of T cells. The KIR detect HLA-I molecules in a peptide-dependent manner, with some KIR displaying exquisite peptide specificity. Studying peptide recognition by KIR often uses TAP-deficient cell lines expressing single HLA-I alleles, which are heterogenous and time consuming to generate. Here, we established an alternative approach using peptide-exchange technologies hitherto developed for studying T cell recognition of HLA-I.</p><p><strong>Methods: </strong>We tested two methods; dipeptide-mediated peptide exchange and \"open-HLA-I\", HLA-I molecules consisting of heavy chain-β₂m disulphide bonded dimers. We combined peptide-exchange technologies with SpyTag-SpyCatcher chemistry to allow rapid detection of KIR binding via HLA-I displayed on plates or cells.</p><p><strong>Results: </strong>We demonstrated the fidelity of this system with peptides of known KIR specificity bound to HLA-C*05:01. We then screened a peptide library to identify novel strong KIR2DS4 binding peptides presented by HLA-C*04:01. Peptide-exchanged HLA-C was functionally competent, promoting activation of KIR2DS4+ NK cells and inhibiting activation of KIR2DL1+ NK cells.</p><p><strong>Conclusion: </strong>Together, we show that peptide-exchangeable HLA-I molecules are ligands for KIR, presenting a flexible, efficient system for examining the peptide sequence dependent recognition of HLA-I by KIR.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag010"},"PeriodicalIF":0.0,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148254150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profiling of porcine B-cell receptor heavy-chain repertoires indicates the development of a wide public pseudorabies virus-specific immune response after vaccination and challenge.","authors":"Valentin Herbet, Edouard Hirchaud, Yannick Blanchard, Véronique Beven, Léon-Charles Tranchevent, Michael Jarman, Bharti Mittal, Céline Deblanc, Frédéric Paboeuf, John A Hammond, Nicolas Eterradossi, Daniel Dory, Marie Bonnet-Di Placido","doi":"10.1093/discim/kyag009","DOIUrl":"10.1093/discim/kyag009","url":null,"abstract":"<p><strong>Introduction: </strong>The antibody repertoire reflects the immune history of an individual. In the present study, we characterized the porcine antibody heavy-chain repertoire following vaccination and challenge with pseudorabies virus (PRV). Due to the limited number and diversity of porcine germline V-genes, we sought to also identify and quantify the public antibody response to different strains that could indicate conserved epitopes.</p><p><strong>Methods: </strong>Three groups, each with four specific pathogen-free pigs were vaccinated twice with the Bartha K61 strain and subsequently challenged twice, each group with a different PRV strain. Longitudinal blood sampling was performed before immunization and at multiple time points chosen to coincide with expected peaks of antigen-specific B cell clonal expansion. Bulk heavy-chain repertoire sequencing was carried out and analysed using the Immunoglobulin Multi-species Annotation Tool, and heavy-chain amino acid sequences were clustered. This approach allowed the identification of B-cell receptor (BCR) populations sharing more than 96% identity in their complementary determining regions, suggesting similar pathogen recognition capabilities.</p><p><strong>Results: </strong>By selecting clusters with frequency kinetics matching immunization or infection events, we identified numerous public clusters shared between pigs within and across groups. Notably, several clusters were detected in more than eight animals, and two clusters were shared by all twelve pigs.</p><p><strong>Conclusion: </strong>Although the selected clusters represent only a subset of the putative PRV-induced repertoire, these findings reveal a striking degree of convergence in the antibody response to PRV in pigs. This work demonstrates that cluster kinetics analysis of bulk BCR sequencing data can identify candidate antigen-specific antibody heavy-chain lineages and provides a framework for future discovery of PRV-specific antibodies.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag009"},"PeriodicalIF":0.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13225268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148152032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional responses of lymphoid stromal cells to Toll-like receptor stimuli <i>in vitro</i>.","authors":"Isabella Cinti, Kassandra Vezyrgianni, Alice E Denton","doi":"10.1093/discim/kyag008","DOIUrl":"10.1093/discim/kyag008","url":null,"abstract":"<p><strong>Introduction: </strong>Lymphoid stromal cells control the spatial organization of lymphoid tissues and respond dynamically during immune reactions, undergoing transcriptional and phenotypic changes that can influence immune responses. The exogenous signals to which lymphoid stromal cells respond, and how, are still being defined.</p><p><strong>Methods: </strong>Lymphoid stromal cells express Toll-like receptors (TLRs), but it has been difficult to separate the role of the stromal cell response to TLR ligands from that of immune cells. To understand this better, we established a method to culture primary lymphoid stromal cells to study their behaviour <i>in vitro</i>.</p><p><strong>Results: </strong>We found that co-culturing fibroblasts with lymphatic endothelial cells produced the most stable cultures, in contrast to pure fibroblast cultures. Lymphoid stromal cells directly sensed TLR ligands, upregulating the cell adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in response to TLR3 and TLR4 stimulation. Lymphoid stromal cells also secreted cytokines and chemokines in response to TLR4 ligation.</p><p><strong>Conclusion: </strong>Lymphoid stromal cells can respond directly to pathogen- and damage-associated molecules, potentially modulating the immunological outcome.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag008"},"PeriodicalIF":0.0,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13170696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147944214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR2^- T peripheral helper cells as potential coordinators of local immune architecture in human cancer.","authors":"Celia Del Carmen Crespo Oliva, Zoé Gerber, Dominique Jean, Hugues Allard-Chamard, Marilyne Labrie","doi":"10.1093/discim/kyag007","DOIUrl":"10.1093/discim/kyag007","url":null,"abstract":"<p><strong>Introduction: </strong>Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet tumor progression remains a challenge, necessitating improved patient stratification and therapeutic strategies. Tumor growth releases neoantigens that activate adaptive immunity, promoting tertiary lymphoid structure (TLS) formation through B- and T-cell interactions. T follicular helper (Tfh) cells are key in coordinating B-cell responses and are linked to favorable outcomes. A newer subset, T peripheral helper (Tph) cells, shares functional traits with Tfh cells but differs in transcriptional and migratory profiles. Though observed in various cancers, their distribution and role in tumor immunity are not fully understood.</p><p><strong>Methods: </strong>To investigate this, a multiplex cyclic immunofluorescence assay was developed to detect and spatially analyze Tph cells in tumors.</p><p><strong>Results: </strong>This revealed three CXCL13-expressing CD4⁺ T-cell subsets: Tfh, Tph, and a 'C-C motif chemokine receptor 2 (CCR2)^- Tph-like' population which, in contrast to the classically CCR2-enriched Tph phenotype described in inflamed tissues, shows markedly reduced CCR2 expression. Downregulation of CXCR5 and CCR2 near CCR2^- Tph-like cells suggested a shift toward local immune residency, forming immune niches. These niches were enriched with pro-inflammatory cells, including Th1, Th17, CD4⁺, CD8⁺ T cells, and B cells. Spatial profiling showed CCR2^- Tph-like cells embedded in an immunoregulatory network, marked by CD69 and inhibitory checkpoints B7-H3 and PD-L1 on surrounding cells.</p><p><strong>Conclusions: </strong>This dual signaling suggests CCR2^- Tph-like cells may modulate tumor immunity by balancing activation and suppression, with potential implications for checkpoint blockade therapy.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"5 1","pages":"kyag007"},"PeriodicalIF":0.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13058833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}