Peng Shao, Regina M. Antonetti, Tina Arkee, Emma L. Hornick, Hai Hui Xue, Gail A. Bishop, Noah S. Butler
CD4+ T follicular helper (TFH) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate TFH cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for TFH cell differentiation and function during systemic inflammatory infections. Loss of CD4+ T cell–intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for TFH cell initiation and instead augmented TH1 development and function. TRAF3-deficient CD4+ T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue TFH cell differentiation. Human CD4+ T cells lacking TRAF3 exhibited impaired TFH polarization, supporting a conserved mechanism by which TRAF3 regulates CD4+ T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the TFH cell specification during infection.
{"title":"TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R–BCL6 signaling nexus","authors":"Peng Shao, Regina M. Antonetti, Tina Arkee, Emma L. Hornick, Hai Hui Xue, Gail A. Bishop, Noah S. Butler","doi":"","DOIUrl":"","url":null,"abstract":"<div >CD4<sup>+</sup> T follicular helper (T<sub>FH</sub>) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate T<sub>FH</sub> cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for T<sub>FH</sub> cell differentiation and function during systemic inflammatory infections. Loss of CD4<sup>+</sup> T cell–intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for T<sub>FH</sub> cell initiation and instead augmented T<sub>H</sub>1 development and function. TRAF3-deficient CD4<sup>+</sup> T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue T<sub>FH</sub> cell differentiation. Human CD4<sup>+</sup> T cells lacking TRAF3 exhibited impaired T<sub>FH</sub> polarization, supporting a conserved mechanism by which TRAF3 regulates CD4<sup>+</sup> T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the T<sub>FH</sub> cell specification during infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424394","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}
Vaccines deliver an immunogen in a manner designed to safely provoke an immune response, leading to the generation of memory T and B cells and long-lived antibody-producing plasma cells. Adjuvants play a critical role in vaccines by controlling how the immune system is exposed to the immunogen and providing inflammatory cues that enable productive immune priming. However, mechanisms of action underlying adjuvant function at the molecular, cell, and tissue levels are diverse and often poorly understood. Here, we review the current understanding of mechanisms of action underlying adjuvants used in subunit protein/polysaccharide vaccines and mRNA vaccines, discuss where possible how these mechanisms of action link to downstream effects on the immune response, and identify knowledge gaps that will be important to fill in order to enable the continued development of more effective adjuvants for challenging pathogens such as HIV and emerging threats.
{"title":"Linking vaccine adjuvant mechanisms of action to function.","authors":"Elana Ben-Akiva, Asheley Chapman, Tianyang Mao, Darrell J Irvine","doi":"10.1126/sciimmunol.ado5937","DOIUrl":"https://doi.org/10.1126/sciimmunol.ado5937","url":null,"abstract":"<p><p>Vaccines deliver an immunogen in a manner designed to safely provoke an immune response, leading to the generation of memory T and B cells and long-lived antibody-producing plasma cells. Adjuvants play a critical role in vaccines by controlling how the immune system is exposed to the immunogen and providing inflammatory cues that enable productive immune priming. However, mechanisms of action underlying adjuvant function at the molecular, cell, and tissue levels are diverse and often poorly understood. Here, we review the current understanding of mechanisms of action underlying adjuvants used in subunit protein/polysaccharide vaccines and mRNA vaccines, discuss where possible how these mechanisms of action link to downstream effects on the immune response, and identify knowledge gaps that will be important to fill in order to enable the continued development of more effective adjuvants for challenging pathogens such as HIV and emerging threats.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":"eado5937"},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417149","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}
Pub Date : 2025-02-14DOI: 10.1126/sciimmunol.adr0517
Peng Shao, Regina M Antonetti, Tina Arkee, Emma L Hornick, Hai Hui Xue, Gail A Bishop, Noah S Butler
CD4+ T follicular helper (TFH) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate TFH cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for TFH cell differentiation and function during systemic inflammatory infections. Loss of CD4+ T cell-intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for TFH cell initiation and instead augmented TH1 development and function. TRAF3-deficient CD4+ T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue TFH cell differentiation. Human CD4+ T cells lacking TRAF3 exhibited impaired TFH polarization, supporting a conserved mechanism by which TRAF3 regulates CD4+ T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the TFH cell specification during infection.
{"title":"TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R-BCL6 signaling nexus.","authors":"Peng Shao, Regina M Antonetti, Tina Arkee, Emma L Hornick, Hai Hui Xue, Gail A Bishop, Noah S Butler","doi":"10.1126/sciimmunol.adr0517","DOIUrl":"10.1126/sciimmunol.adr0517","url":null,"abstract":"<p><p>CD4<sup>+</sup> T follicular helper (T<sub>FH</sub>) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate T<sub>FH</sub> cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for T<sub>FH</sub> cell differentiation and function during systemic inflammatory infections. Loss of CD4<sup>+</sup> T cell-intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for T<sub>FH</sub> cell initiation and instead augmented T<sub>H</sub>1 development and function. TRAF3-deficient CD4<sup>+</sup> T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue T<sub>FH</sub> cell differentiation. Human CD4<sup>+</sup> T cells lacking TRAF3 exhibited impaired T<sub>FH</sub> polarization, supporting a conserved mechanism by which TRAF3 regulates CD4<sup>+</sup> T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the T<sub>FH</sub> cell specification during infection.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":"eadr0517"},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417150","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}
Elana Ben-Akiva, Asheley Chapman, Tianyang Mao, Darrell J. Irvine
Vaccines deliver an immunogen in a manner designed to safely provoke an immune response, leading to the generation of memory T and B cells and long-lived antibody-producing plasma cells. Adjuvants play a critical role in vaccines by controlling how the immune system is exposed to the immunogen and providing inflammatory cues that enable productive immune priming. However, mechanisms of action underlying adjuvant function at the molecular, cell, and tissue levels are diverse and often poorly understood. Here, we review the current understanding of mechanisms of action underlying adjuvants used in subunit protein/polysaccharide vaccines and mRNA vaccines, discuss where possible how these mechanisms of action link to downstream effects on the immune response, and identify knowledge gaps that will be important to fill in order to enable the continued development of more effective adjuvants for challenging pathogens such as HIV and emerging threats.
{"title":"Linking vaccine adjuvant mechanisms of action to function","authors":"Elana Ben-Akiva, Asheley Chapman, Tianyang Mao, Darrell J. Irvine","doi":"","DOIUrl":"","url":null,"abstract":"<div >Vaccines deliver an immunogen in a manner designed to safely provoke an immune response, leading to the generation of memory T and B cells and long-lived antibody-producing plasma cells. Adjuvants play a critical role in vaccines by controlling how the immune system is exposed to the immunogen and providing inflammatory cues that enable productive immune priming. However, mechanisms of action underlying adjuvant function at the molecular, cell, and tissue levels are diverse and often poorly understood. Here, we review the current understanding of mechanisms of action underlying adjuvants used in subunit protein/polysaccharide vaccines and mRNA vaccines, discuss where possible how these mechanisms of action link to downstream effects on the immune response, and identify knowledge gaps that will be important to fill in order to enable the continued development of more effective adjuvants for challenging pathogens such as HIV and emerging threats.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424387","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}
Pub Date : 2025-02-07DOI: 10.1126/sciimmunol.adp6667
Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold
The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow–confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.
{"title":"Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma","authors":"Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold","doi":"10.1126/sciimmunol.adp6667","DOIUrl":"https://doi.org/10.1126/sciimmunol.adp6667","url":null,"abstract":"The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow–confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"63 10 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258318","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}
Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals
Parasitic helminths induce the production of interleukin-4 (IL-4), which causes the expansion of virtual memory CD8+ T cells (TVM cells), a cell subset that contributes to the control of coinfection with intracellular pathogens. However, the mechanisms regulating IL-4–dependent TVM cell activation and expansion remain ill defined. Here, we used single-cell RNA sequencing of CD8+ T cells to identify pathways that control IL-4–dependent TVM cell responses. Gene signature analysis of CD8+ T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a selective surface marker of IL-4–induced TVM cells. CD22+ TVM cells were enriched for interferon-γ and granzyme A and retained a diverse TCR repertoire while enriched in self-reactive CDR3 sequences. CD22 intrinsically regulated the IL-4–induced CD8+ T cell effector program, resulting in reduced responsiveness of CD22+ TVM cells and regulatory functions to infection and inflammation. Thus, helminth-induced IL-4 drives the expansion and activation of TVM cells that is counterinhibited by CD22.
{"title":"IL-4 induces CD22 expression to restrain the effector program of virtual memory T cells","authors":"Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals","doi":"","DOIUrl":"","url":null,"abstract":"<div >Parasitic helminths induce the production of interleukin-4 (IL-4), which causes the expansion of virtual memory CD8<sup>+</sup> T cells (T<sub>VM</sub> cells), a cell subset that contributes to the control of coinfection with intracellular pathogens. However, the mechanisms regulating IL-4–dependent T<sub>VM</sub> cell activation and expansion remain ill defined. Here, we used single-cell RNA sequencing of CD8<sup>+</sup> T cells to identify pathways that control IL-4–dependent T<sub>VM</sub> cell responses. Gene signature analysis of CD8<sup>+</sup> T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a selective surface marker of IL-4–induced T<sub>VM</sub> cells. CD22<sup>+</sup> T<sub>VM</sub> cells were enriched for interferon-γ and granzyme A and retained a diverse TCR repertoire while enriched in self-reactive CDR3 sequences. CD22 intrinsically regulated the IL-4–induced CD8<sup>+</sup> T cell effector program, resulting in reduced responsiveness of CD22<sup>+</sup> T<sub>VM</sub> cells and regulatory functions to infection and inflammation. Thus, helminth-induced IL-4 drives the expansion and activation of T<sub>VM</sub> cells that is counterinhibited by CD22.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363129","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}
Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska
Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01–restricted nucleoprotein (NP)418–426 epitopes (B*35:01-NP418) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP418 variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP418+CD8+ T cell lines displayed reduced cross-reactivity in the absence of CD8 coreceptor binding, validating the low avidity of cross-reactive B*35:01-NP418+CD8+ T cell responses. Six TCR–HLA-B*35:01/NP418 crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP418 epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP418 epitope. Our study defines molecular mechanisms associated with extensive TCR cross-reactivity toward naturally occurring viral variants highly relevant to universal protective immunity against influenza.
{"title":"Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors","authors":"Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska","doi":"","DOIUrl":"","url":null,"abstract":"<div >Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01–restricted nucleoprotein (NP)<sub>418–426</sub> epitopes (B*35:01-NP<sub>418</sub>) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP<sub>418</sub> variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP<sub>418</sub><sup>+</sup>CD8<sup>+</sup> T cell lines displayed reduced cross-reactivity in the absence of CD8 coreceptor binding, validating the low avidity of cross-reactive B*35:01-NP<sub>418</sub><sup>+</sup>CD8<sup>+</sup> T cell responses. Six TCR–HLA-B*35:01/NP<sub>418</sub> crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP<sub>418</sub> epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP<sub>418</sub> epitope. Our study defines molecular mechanisms associated with extensive TCR cross-reactivity toward naturally occurring viral variants highly relevant to universal protective immunity against influenza.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn3805","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363115","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}
Pub Date : 2025-02-07DOI: 10.1126/sciimmunol.adw3641
Daniel A Shapiro, Christopher A Hunter
Commensals induce germinal center-like structures in the skin that can be used for vaccination.
{"title":"Afraid of needles? Try lotion: Engineering skin commensals for vaccination.","authors":"Daniel A Shapiro, Christopher A Hunter","doi":"10.1126/sciimmunol.adw3641","DOIUrl":"https://doi.org/10.1126/sciimmunol.adw3641","url":null,"abstract":"<p><p>Commensals induce germinal center-like structures in the skin that can be used for vaccination.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":"eadw3641"},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371033","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}
Pub Date : 2025-02-07DOI: 10.1126/sciimmunol.adn3805
Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska
Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01–restricted nucleoprotein (NP) 418–426 epitopes (B*35:01-NP 418 ) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP 418 variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP 418+ CD8 + T cell lines displayed reduced cross-reactivity in the absence of CD8 coreceptor binding, validating the low avidity of cross-reactive B*35:01-NP 418+ CD8 + T cell responses. Six TCR–HLA-B*35:01/NP 418 crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP 418 epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP 418 epitope. Our study defines molecular mechanisms associated with extensive TCR cross-reactivity toward naturally occurring viral variants highly relevant to universal protective immunity against influenza.
{"title":"Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors","authors":"Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska","doi":"10.1126/sciimmunol.adn3805","DOIUrl":"https://doi.org/10.1126/sciimmunol.adn3805","url":null,"abstract":"Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01–restricted nucleoprotein (NP) <jats:sub>418–426</jats:sub> epitopes (B*35:01-NP <jats:sub>418</jats:sub> ) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP <jats:sub>418</jats:sub> variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP <jats:sub>418</jats:sub> <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cell lines displayed reduced cross-reactivity in the absence of CD8 coreceptor binding, validating the low avidity of cross-reactive B*35:01-NP <jats:sub>418</jats:sub> <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cell responses. Six TCR–HLA-B*35:01/NP <jats:sub>418</jats:sub> crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP <jats:sub>418</jats:sub> epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP <jats:sub>418</jats:sub> epitope. Our study defines molecular mechanisms associated with extensive TCR cross-reactivity toward naturally occurring viral variants highly relevant to universal protective immunity against influenza.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258317","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}
Commensals induce germinal center–like structures in the skin that can be used for vaccination.
{"title":"Afraid of needles? Try lotion: Engineering skin commensals for vaccination","authors":"Daniel A. Shapiro, Christopher A. Hunter","doi":"","DOIUrl":"","url":null,"abstract":"<div >Commensals induce germinal center–like structures in the skin that can be used for vaccination.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363137","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号