ImmunityPub Date : 2026-08-11DOI: 10.1016/j.immuni.2026.07.013
Taylor A Graham, Peter A Savage
{"title":"Peripheral vision: Treg cell induction in the gut.","authors":"Taylor A Graham, Peter A Savage","doi":"10.1016/j.immuni.2026.07.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.07.013","url":null,"abstract":"<p><p>Some regulatory T (Treg) cells differentiate at peripheral sites in response to antigens derived from innocuous sources. In this issue of Immunity, Chi et al. examine an extensive array of T cell receptors with specificity for self, microbial, or dietary antigens to define the rules governing peripheral Treg cell differentiation.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"59 8","pages":"2061-2063"},"PeriodicalIF":30.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-11Epub Date: 2026-07-28DOI: 10.1016/j.immuni.2026.07.001
Xinxin Chi, Charlotte H Wang, Yollanda Franco Parisotto, William A Nyberg, Vanja Cabric, Adelaide Gelineau, Yi Cao, David L Owen, Jonas Ambjörnsson, Diane Mathis, Justin Eyquem, Chrysothemis C Brown, Christophe Benoist
{"title":"TCR origin and specificity to environmental or self-antigens on distinct antigen-presenting cells determine peripheral Treg cell differentiation.","authors":"Xinxin Chi, Charlotte H Wang, Yollanda Franco Parisotto, William A Nyberg, Vanja Cabric, Adelaide Gelineau, Yi Cao, David L Owen, Jonas Ambjörnsson, Diane Mathis, Justin Eyquem, Chrysothemis C Brown, Christophe Benoist","doi":"10.1016/j.immuni.2026.07.001","DOIUrl":"10.1016/j.immuni.2026.07.001","url":null,"abstract":"<p><p>Peripheral differentiation of regulatory T (pTreg) cells promotes immunological tolerance to obligate non-self, such as food or symbiotic microbes. We examined the relative importance of TCR recognition vs. environmental cues, leveraging CRISPR-based TCR editing of primary T cells with a large TCR panel, assessing pTreg cell differentiation induced by self-, microbial, or dietary antigens. All antigen classes drove stable pTreg cell differentiation, which varied with TCR origin: TCRs derived from Treg cells enabled pTreg cell differentiation more effectively than those from conventional T cells. TCRs recognizing self-, microbial, or dietary antigens elicited distinct pTreg cell phenotypes: Helios⁺, RORγ⁺, or both. Different TCR-antigen pairs established distinct transcriptional programs. These differences traced to the types of antigen-presenting cells (APCs) involved-food-reactive TCRs depended predominantly on RORγ⁺ APCs and self-reactive TCRs depended on conventional dendritic cells. Thus, TCR specificity is a primary determinant of CD4<sup>+</sup> T cell fate and phenotype, integrating antigen specificity and presentation context, providing a framework to design TCR-based tolerogenic immunotherapies.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2266-2281.e6"},"PeriodicalIF":30.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13420020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148602402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-11Epub Date: 2026-07-02DOI: 10.1016/j.immuni.2026.06.003
Catarina Gago da Graça, Yuxi Cao, Sining Li, Anna F Lindemann, Leonie Heyden, Sharanya K M Wijesinghe, Annika Poch, Minh-Hanh T Nguyen, Nhat T Huynh-Anh, Elena Daum, Danielle Chen, Carlson Tsui, Erandi Rupasinghe, Michael P Gantier, Axel Roers, Robert Thimme, Maike Hofmann, Sammy Bedoui, Zeinab Abdullah, Jan Schröder, Axel Kallies, Yannick O Alexandre, Daniel T Utzschneider
{"title":"B cell-derived type I interferon sustains T cell functionality upon strong TCR stimulation during chronic infection.","authors":"Catarina Gago da Graça, Yuxi Cao, Sining Li, Anna F Lindemann, Leonie Heyden, Sharanya K M Wijesinghe, Annika Poch, Minh-Hanh T Nguyen, Nhat T Huynh-Anh, Elena Daum, Danielle Chen, Carlson Tsui, Erandi Rupasinghe, Michael P Gantier, Axel Roers, Robert Thimme, Maike Hofmann, Sammy Bedoui, Zeinab Abdullah, Jan Schröder, Axel Kallies, Yannick O Alexandre, Daniel T Utzschneider","doi":"10.1016/j.immuni.2026.06.003","DOIUrl":"10.1016/j.immuni.2026.06.003","url":null,"abstract":"<p><p>B cells are highly abundant lymphocytes and central players in humoral immunity. Although T cells are well known to support humoral responses, how B cells influence T cell responses is less understood. Here, we show that B cells are critical for CD8<sup>+</sup> T cell responses to chronic, but not acute, viral infections. In the absence of B cells, T cells responding to chronic infection exhibited severely impaired effector differentiation. This dependency on B cell help was dictated by high antigen loads and strong T cell receptor (TCR) stimulation. Loss of either B cells or interferon-I (IFN-I) signaling led to severe functional deficits in exhausted T cells, implicating B cells as key producers of IFN-I. The IFN-I-dependent T cell response to strong TCR stimulation is mediated, in part, by the transcription factor IRF1. Therefore, during chronic infection, we uncover an important role for B cell-derived IFN-I in modulating T cell responses to strong TCR stimulation.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2199-2214.e7"},"PeriodicalIF":30.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-11Epub Date: 2026-06-12DOI: 10.1016/j.immuni.2026.05.012
Barnabas G Williams, Jordan R Barrett, Josefin Bartholdson Scott, Cassandra A Rigby, Matteo Cagiada, Doris Quinkert, Kirsty McHugh, Anna Huhn, Sean A Burnap, Camille Gourjault, Francesca Byrne, Sai Sundar Rajan Raghavan, Ana Rodrigues, Laura Bergamaschi, Beatrice Balzarotti, Simon Watson, Noah Miller, Lloyd D W King, Francesca R Donnellan, Camilla A Gladstone, Jemima Paterson, Stefania Scalabrino, Sarah E Silk, Jo Salkeld, Angela M Minassian, Katherine Skinner, Weston B Struwe, Charlotte M Deane, Stephen T Reece, Andrew B Ward, Simon J Draper
{"title":"Analysis of monoclonal antibodies against the malaria invasion complex protein RIPR reveals the structural basis for synergistic antibody protection.","authors":"Barnabas G Williams, Jordan R Barrett, Josefin Bartholdson Scott, Cassandra A Rigby, Matteo Cagiada, Doris Quinkert, Kirsty McHugh, Anna Huhn, Sean A Burnap, Camille Gourjault, Francesca Byrne, Sai Sundar Rajan Raghavan, Ana Rodrigues, Laura Bergamaschi, Beatrice Balzarotti, Simon Watson, Noah Miller, Lloyd D W King, Francesca R Donnellan, Camilla A Gladstone, Jemima Paterson, Stefania Scalabrino, Sarah E Silk, Jo Salkeld, Angela M Minassian, Katherine Skinner, Weston B Struwe, Charlotte M Deane, Stephen T Reece, Andrew B Ward, Simon J Draper","doi":"10.1016/j.immuni.2026.05.012","DOIUrl":"10.1016/j.immuni.2026.05.012","url":null,"abstract":"<p><p>Plasmodium falciparum RH5-interacting protein (RIPR) is central to the essential PTRAMP-CSS-RIPR-CyRPA-RH5 (PCRCR) complex, a leading target of blood-stage malaria vaccines. However, mechanisms whereby anti-RIPR antibodies inhibit parasite invasion are poorly understood. We characterized 83 human IgG monoclonal antibodies (mAbs) from RIPR-vaccinated Kymouse platform mice. Single mAbs had minimal neutralizing activity; however, high-level synergistic inhibition was observed with pools of mAbs targeting the RIPR-tail region. Structural characterization and molecular dynamics simulations of RIPR-tail showed that mAbs targeting epidermal growth factor (EGF)-like domains 6-8 (RIPR<sup>EGF (6-8)</sup>), but not RIPR<sup>EGF (9-10)</sup> or the C-terminal domain (RIPR<sup>CTD</sup>), synergized to constrain the RIPR-tail conformation. The same antibodies dissociated PTRAMP-CSS from RIPR, thereby enabling anti-RIPR<sup>EGF (9-10)-CTD</sup> mAbs or anti-CSS single-domain Abs to bind and potentiate anti-RIPR<sup>EGF (6-8)</sup> IgG. Addition of these mAbs to IgG from humans immunized with the R78C (RIPR<sup>EGF (7-8)</sup>-CyRPA) candidate vaccine enhanced malaria growth inhibition. These data provide a framework to guide next-generation blood-stage malaria vaccine design.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2106-2121.e10"},"PeriodicalIF":30.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-11DOI: 10.1016/j.immuni.2026.07.012
Ewelina Sobierajska, Christopher B Medina
{"title":"The cost of persistence: MEK and metabolic demand.","authors":"Ewelina Sobierajska, Christopher B Medina","doi":"10.1016/j.immuni.2026.07.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.07.012","url":null,"abstract":"<p><p>The metabolic mechanisms linking chronic TCR stimulation to T cell exhaustion remain incompletely understood. Mitra and colleagues show that sustained MEK signaling drives the bioenergetic demands of chronic activation to promote terminal exhaustion, whereas MEK inhibition maintains progenitor-like T cells.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"59 8","pages":"2058-2060"},"PeriodicalIF":30.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-11Epub Date: 2026-06-12DOI: 10.1016/j.immuni.2026.05.015
Dandan Yang, Linglin Huang, Hanning Cheng, Nandini Acharya, Davide Mangani, Yong Hu, Dan Hu, Alissa J Nelson, Jian Min Ren, Vicky Yang, Junrong Xia, Linfeng Le, Yifan Cai, Yufan Wu, Alexandra Schnell, Rajesh K Krishnan, Shrishti Saxena, Mariann Polgar-Turcsanyi, Tanuja Chitnis, Matthew P Stokes, Clare M Baecher-Allan, Raymond A Sobel, Vijay K Kuchroo, Ana C Anderson
{"title":"A cell-intrinsic glucocorticoid biosynthesis and sensing circuit maintains a homeostatic Th17 cell state.","authors":"Dandan Yang, Linglin Huang, Hanning Cheng, Nandini Acharya, Davide Mangani, Yong Hu, Dan Hu, Alissa J Nelson, Jian Min Ren, Vicky Yang, Junrong Xia, Linfeng Le, Yifan Cai, Yufan Wu, Alexandra Schnell, Rajesh K Krishnan, Shrishti Saxena, Mariann Polgar-Turcsanyi, Tanuja Chitnis, Matthew P Stokes, Clare M Baecher-Allan, Raymond A Sobel, Vijay K Kuchroo, Ana C Anderson","doi":"10.1016/j.immuni.2026.05.015","DOIUrl":"10.1016/j.immuni.2026.05.015","url":null,"abstract":"<p><p>T helper 17 (Th17) cells are heterogeneous: homeostatic Th17 (Th17<sub>Hom</sub>) cells maintain tissue homeostasis, and pro-inflammatory Th17 (Th17<sub>Inf</sub>) cells drive autoimmune inflammation. IL-23 drives Th17<sub>Inf</sub>, but the signals that maintain Th17<sub>Hom</sub> remain unclear. Here, we found that differential glucocorticoid (GC) production downstream of CYP11A1, a critical enzyme for steroidogenesis, distinguished Th17<sub>Hom</sub> cells from Th17<sub>Inf</sub> cells. Although TCR signaling opened the Cyp11a1 locus, TGF-β1 and IL-6, key cytokines for Th17<sub>Hom</sub> cell differentiation, maintained and amplified Cyp11a1. Th17<sub>Hom</sub> cell-derived GC signaled through the glucocorticoid receptor (GR), which was higher in Th17<sub>Hom</sub> cells compared with Th17<sub>Inf</sub> cells, thereby forming a circuit that maintained the homeostatic state. Integration of multi-omics data from CYP11A1- and GR-deficient Th17<sub>Hom</sub> cells revealed a gene network underlying this circuit. TGF-β1, a key node in the network, restored GC sensing to Th17<sub>Inf</sub>. We thus identify a GC signaling circuit that maintains Th17 homeostasis with implications for treating Th17-mediated autoimmunity.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2232-2249.e10"},"PeriodicalIF":30.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-11Epub Date: 2026-06-23DOI: 10.1016/j.immuni.2026.05.017
Elya A Shamskhou, Fergal J Duffy, Lauren M Cross, Courtney R Plumlee, Benjamin H Gern, Holly W Barrett, Alan H Diercks, Sara B Cohen, Ramya Sivakumar, John D Aitchison, Vitaly V Ganusov, Kevin B Urdahl, Michael Y Gerner
{"title":"Monocytic niches escape T cell surveillance and promote Mycobacterium tuberculosis persistence in lymph nodes.","authors":"Elya A Shamskhou, Fergal J Duffy, Lauren M Cross, Courtney R Plumlee, Benjamin H Gern, Holly W Barrett, Alan H Diercks, Sara B Cohen, Ramya Sivakumar, John D Aitchison, Vitaly V Ganusov, Kevin B Urdahl, Michael Y Gerner","doi":"10.1016/j.immuni.2026.05.017","DOIUrl":"10.1016/j.immuni.2026.05.017","url":null,"abstract":"<p><p>Lung-draining mediastinal lymph nodes (medLNs) are critical for Mycobacterium tuberculosis (Mtb) pathogenesis, serving both as sites of T cell priming and, paradoxically, reservoirs for long-term bacterial persistence. To understand this dichotomy, we examined myeloid and CD4<sup>+</sup> T cell dynamics in medLNs after aerosol Mtb infection. Early bacterial dissemination occurred via monocytes and interleukin (IL)-12-producing conventional dendritic cells (cDCs), which initiated T helper 1 (Th1) cell priming within the T cell zone. Over time, cDC migration and T cell activation declined, and medLNs became dominated by heavily infected monocyte-derived aggregates that persisted into late infection. Despite inducing proinflammatory and bactericidal pathways, these aggregates escaped recognition by Mtb-specific T cells and failed to clear Mtb, thereby forming an immunologically \"blind\" niche. Bacille Calmette-Guérin (BCG) vaccination reduced Mtb burden and niche establishment without altering myeloid trafficking or T cell priming. Thus, Mtb persists in medLNs within monocytic niches, eliciting classical antimicrobial programs that are insufficient for sterilizing control.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2122-2141.e9"},"PeriodicalIF":30.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13379055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-04DOI: 10.1016/j.immuni.2026.07.002
Maria A. Koufaki,Erin Richardson,Eduardo Bonavita,Richard Reeves,Agrin Moeini,Shih-Chieh Chiang,Antonia Banyard,Massimo Russo,Charles H. Earnshaw,Charlotte R. Bell,Eimear Flanagan,Victoria S. Pelly,Laetitia Nebot-Bral,Anna Pidoux,Poppy Dunn,Sudhakar Sahoo,Sandrine Henri,Bernard Malissen,Andrew S. MacDonald,Natalia Moncaut,Santiago Zelenay
{"title":"CCR7+ activated dendritic cells are essential for spontaneous and immunotherapy-driven anti-tumor immunity","authors":"Maria A. Koufaki,Erin Richardson,Eduardo Bonavita,Richard Reeves,Agrin Moeini,Shih-Chieh Chiang,Antonia Banyard,Massimo Russo,Charles H. Earnshaw,Charlotte R. Bell,Eimear Flanagan,Victoria S. Pelly,Laetitia Nebot-Bral,Anna Pidoux,Poppy Dunn,Sudhakar Sahoo,Sandrine Henri,Bernard Malissen,Andrew S. MacDonald,Natalia Moncaut,Santiago Zelenay","doi":"10.1016/j.immuni.2026.07.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.07.002","url":null,"abstract":"Single-cell transcriptomics identifies a convergent activation state of conventional dendritic cells (cDCs) shared by type 1 and type 2 cDCs (cDC1s and cDC2s). These activated DCs (actDCs) are characterized by co-expression of T cell-stimulating and inhibitory molecules. Here, we examined the functional contribution of actDCs to anti-tumor immunity by developing mouse models that leverage CCR7 expression to conditionally label or ablate actDCs. The capacity of cDCs to stimulate tumor-specific cytotoxic T lymphocytes (CTLs) was restricted to the actDC state. cDC1- and cDC2-derived actDCs supported CTL priming through cross-presentation and cross-dressing, respectively, with the latter occurring in a cancer type-dependent manner. actDCs were required for the activation of naive CTLs in tumor-draining lymph nodes and for sustaining effector CTL function within tumors. Consequently, ablation of actDCs impaired spontaneous tumor control and responses to immune checkpoint blockade or adoptive T cell therapy. Thus, the actDC state emerges as a critical determinant of cDC-mediated anti-tumor immunity.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"1 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-04DOI: 10.1016/j.immuni.2026.07.006
Katharina Mauel,Daria Hirschmann,Nelli Blank-Stein,Marie-Louise Diefenbach-Wilke,Theresa Eulgem,Shirley Le,Samuel N. Breit,Miguel P. Soares,Vicky Wang-Wei Tsai,Florent Ginhoux,William R. Heath,Lynette Beattie,Elvira Mass
{"title":"CD163+ red pulp macrophages interact with marginal metallophilic macrophages during blood-stage malaria to maintain splenic architecture","authors":"Katharina Mauel,Daria Hirschmann,Nelli Blank-Stein,Marie-Louise Diefenbach-Wilke,Theresa Eulgem,Shirley Le,Samuel N. Breit,Miguel P. Soares,Vicky Wang-Wei Tsai,Florent Ginhoux,William R. Heath,Lynette Beattie,Elvira Mass","doi":"10.1016/j.immuni.2026.07.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.07.006","url":null,"abstract":"The spleen harbors distinct macrophage subsets that support circulatory homeostasis and initiate immune responses, but the ontogeny and long-term dynamics of these populations remain incompletely understood. Here, we identified a transcriptionally and developmentally distinct CD163-expressing red pulp macrophage (CD163high RPM) population that arose from yolk sac progenitors and occupied a vascular-associated niche. Using fate-mapping models, we showed that CD163− RPMs were progressively replenished by monocytes during aging, whereas CD163high RPMs were mainly self-maintaining. During blood-stage malaria, CD163high RPMs were rapidly depleted, failed to recover despite parasite clearance, and were replaced by CD163− monocyte-derived RPMs. Single-cell RNA sequencing and genetic mouse models revealed that CD163 deficiency exacerbated structural disintegration of the marginal zone and selectively impaired marginal metallophilic macrophage (MMM) recovery, underscoring a CD163-dependent RPM-MMM crosstalk. This study reveals that the sustained loss of a specialized, yolk sac-derived CD163high RPM subset rewires splenic architecture and inter-macrophage crosstalk long after malaria resolution.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"30 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-08-03DOI: 10.1016/j.immuni.2026.07.004
De Dong,Huiling Li,Yuwei Zhu,Zebin Lu,Junliang Zhu,Xinyu Tian,Zhiwei Huang
{"title":"Butyrophilin-like 3 and 8 tetramers clamp Vγ4Vδ1 T cell receptors for antigen-independent activation","authors":"De Dong,Huiling Li,Yuwei Zhu,Zebin Lu,Junliang Zhu,Xinyu Tian,Zhiwei Huang","doi":"10.1016/j.immuni.2026.07.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.07.004","url":null,"abstract":"BTNL3 and BTNL8, butyrophilin-like (BTNL) family receptors, are predominantly expressed on intestinal epithelial cells. The BTNL3-BTNL8 complex selectively activates human Vγ4⁺ T cells, which play critical roles in intestinal immune homeostasis and tissue damage repair. Here, we report the structure of the BTNL3-BTNL8-Vγ4Vδ1 T cell receptor (TCR) complex. The structure reveals that BTNL3-BTNL8 forms an antigen-independent tetramer, in contrast to the phosphoantigen-driven association of BTN2A1-BTN3A1. Two BTNL3-BTNL8 heterodimers clamp a head-to-head TCR homodimer to form a 2:2:2 BTNL3:BTNL8:Vγ4Vδ1 TCR complex, with the Vγ4 HV4 and CDR2 loops jointly engaging BTNL3. Structural alignment indicates that the CD1d binding site on TCR overlaps spatially with one monomer within a TCR dimer, suggesting that TCR dimerization sterically precludes simultaneous engagement of CD1d molecules. Together, our results elucidate the structural mechanism of BTNL3-BTNL8-mediated engagement and activation of Vγ4Vδ1 TCR, offering insights into γδ TCR signaling initiation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"154 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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