Pub Date : 2024-06-03Epub Date: 2024-04-02DOI: 10.1084/jem.20231348
Guilhem Lalle, Raphaëlle Lautraite, Khaled Bouherrou, Maud Plaschka, Aurora Pignata, Allison Voisin, Julie Twardowski, Marlène Perrin-Niquet, Pierre Stéphan, Sarah Durget, Laurie Tonon, Maude Ardin, Cyril Degletagne, Alain Viari, Laurence Belgarbi Dutron, Nathalie Davoust, Thomas S Postler, Jingyao Zhao, Christophe Caux, Julie Caramel, Stéphane Dalle, Philippe A Cassier, Ulf Klein, Marc Schmidt-Supprian, Roland Liblau, Sankar Ghosh, Yenkel Grinberg-Bleyer
The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4+ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-κB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies.
{"title":"NF-κB subunits RelA and c-Rel selectively control CD4+ T cell function in multiple sclerosis and cancer.","authors":"Guilhem Lalle, Raphaëlle Lautraite, Khaled Bouherrou, Maud Plaschka, Aurora Pignata, Allison Voisin, Julie Twardowski, Marlène Perrin-Niquet, Pierre Stéphan, Sarah Durget, Laurie Tonon, Maude Ardin, Cyril Degletagne, Alain Viari, Laurence Belgarbi Dutron, Nathalie Davoust, Thomas S Postler, Jingyao Zhao, Christophe Caux, Julie Caramel, Stéphane Dalle, Philippe A Cassier, Ulf Klein, Marc Schmidt-Supprian, Roland Liblau, Sankar Ghosh, Yenkel Grinberg-Bleyer","doi":"10.1084/jem.20231348","DOIUrl":"10.1084/jem.20231348","url":null,"abstract":"<p><p>The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4+ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-κB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10986815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335853","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 : 2024-06-03Epub Date: 2024-05-06DOI: 10.1084/jem.2023238704302024c
Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic
{"title":"Correction: Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.","authors":"Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic","doi":"10.1084/jem.2023238704302024c","DOIUrl":"10.1084/jem.2023238704302024c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11075643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140870428","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 : 2024-06-03Epub Date: 2024-04-10DOI: 10.1084/jem.20240389
Silvia Pires, Randy S Longman
Environmental airborne antigens are central to the development of allergic asthma, but the cellular processes that trigger disease remain incompletely understood. In this report, Schmitt et al. (https://doi.org/10.1084/jem.20231236) identify TNF-like protein 1A (TL1A) as an epithelial alarmin constitutively expressed by a subset of lung epithelial cells, which is released in response to airborne microbial challenge and synergizes with IL-33 to drive allergic disease.
{"title":"Sounding the alarm in the lung with TL1A.","authors":"Silvia Pires, Randy S Longman","doi":"10.1084/jem.20240389","DOIUrl":"https://doi.org/10.1084/jem.20240389","url":null,"abstract":"<p><p>Environmental airborne antigens are central to the development of allergic asthma, but the cellular processes that trigger disease remain incompletely understood. In this report, Schmitt et al. (https://doi.org/10.1084/jem.20231236) identify TNF-like protein 1A (TL1A) as an epithelial alarmin constitutively expressed by a subset of lung epithelial cells, which is released in response to airborne microbial challenge and synergizes with IL-33 to drive allergic disease.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11010314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140870429","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 : 2024-06-03Epub Date: 2024-04-02DOI: 10.1084/jem.20232094
Francesca Lucibello, Ana I Lalanne, Anne-Laure Le Gac, Abdoulaye Soumare, Setareh Aflaki, Joanna Cyrta, Lea Dubreuil, Martin Mestdagh, Marion Salou, Alexandre Houy, Christina Ekwegbara, Camille Jamet, Sophie Gardrat, Anais Le Ven, Karine Bernardeau, Nathalie Cassoux, Alexandre Matet, Denis Malaise, Gaelle Pierron, Sophie Piperno-Neumann, Marc-Henri Stern, Manuel Rodrigues, Olivier Lantz
Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage.
葡萄膜黑色素瘤(UM)是最常见的眼癌。3 号染色体(M3)缺失与高转移风险有关。与低风险的 3 号染色体缺失(D3)肿瘤相比,M3 肿瘤的 T 淋巴细胞浸润更多,这与其他肿瘤类型形成鲜明对比,后者的 T 细胞浸润与较好的预后有关。这些 T 细胞是否代表一种抗肿瘤反应,以及这些 T 细胞如何在眼部被激活,这些都是未知数。在这里,我们描述了浸润原发性 UMs 的 T 细胞的特征。M3肿瘤中的CD8+细胞和Treg细胞比D3肿瘤中的更多。CD39+PD-1+CD8+T细胞在M3肿瘤中富集,表明对肿瘤抗原(Ag)有特异性反应,这一点已通过HLA-A2:Melan-A四聚体得到证实。T细胞的scRNAseq-VDJ分析表明CD39+PD1+CD8+克隆扩增数量较多,表明原位抗肿瘤Ag反应。TCRseq和肿瘤-Ag四聚体染色描述了M3和D3肿瘤中抗肿瘤反应的再循环模式。因此,肿瘤-Ag 反应发生在局部 UMs 中,这就提出了在没有已知淋巴引流的情况下的启动机制问题。
{"title":"Divergent local and systemic antitumor response in primary uveal melanomas.","authors":"Francesca Lucibello, Ana I Lalanne, Anne-Laure Le Gac, Abdoulaye Soumare, Setareh Aflaki, Joanna Cyrta, Lea Dubreuil, Martin Mestdagh, Marion Salou, Alexandre Houy, Christina Ekwegbara, Camille Jamet, Sophie Gardrat, Anais Le Ven, Karine Bernardeau, Nathalie Cassoux, Alexandre Matet, Denis Malaise, Gaelle Pierron, Sophie Piperno-Neumann, Marc-Henri Stern, Manuel Rodrigues, Olivier Lantz","doi":"10.1084/jem.20232094","DOIUrl":"10.1084/jem.20232094","url":null,"abstract":"<p><p>Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10986814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335851","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 : 2024-06-03Epub Date: 2024-05-13DOI: 10.1084/jem.2023124405032024c
Lucas F Loffredo, Thomas M Savage, Olivia R Ringham, Nicholas Arpaia
{"title":"Correction: Treg-tissue cell interactions in repair and regeneration.","authors":"Lucas F Loffredo, Thomas M Savage, Olivia R Ringham, Nicholas Arpaia","doi":"10.1084/jem.2023124405032024c","DOIUrl":"10.1084/jem.2023124405032024c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11089750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912172","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 : 2024-06-03Epub Date: 2024-05-21DOI: 10.1084/jem.20240813
Lucie Van Emmenis
Irene Salinas is a professor in the Department of Biology, University of New Mexico. Her lab uses multiple animal models to study nasal immunity and neuroimmune interactions in the olfactory-central nervous system axis in response to microorganisms. We recently spoke with Irene about her current work, her diversity, equity, and inclusion (DEI) work, and how her leadership style has changed over the years.
{"title":"Irene Salinas: The joy of continuous growth and learning.","authors":"Lucie Van Emmenis","doi":"10.1084/jem.20240813","DOIUrl":"10.1084/jem.20240813","url":null,"abstract":"<p><p>Irene Salinas is a professor in the Department of Biology, University of New Mexico. Her lab uses multiple animal models to study nasal immunity and neuroimmune interactions in the olfactory-central nervous system axis in response to microorganisms. We recently spoke with Irene about her current work, her diversity, equity, and inclusion (DEI) work, and how her leadership style has changed over the years.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074679","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 : 2024-06-03Epub Date: 2024-04-02DOI: 10.1084/jem.20232387
Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic
Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.
{"title":"Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.","authors":"Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic","doi":"10.1084/jem.20232387","DOIUrl":"10.1084/jem.20232387","url":null,"abstract":"<p><p>Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10986756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335852","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 : 2024-06-03Epub Date: 2024-04-10DOI: 10.1084/jem.20231236
Pauline Schmitt, Anais Duval, Mylène Camus, Emma Lefrançais, Stéphane Roga, Cécile Dedieu, Nathalie Ortega, Elisabeth Bellard, Emilie Mirey, Emmanuelle Mouton-Barbosa, Odile Burlet-Schiltz, Anne Gonzalez-de-Peredo, Corinne Cayrol, Jean-Philippe Girard
Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low "ILC9" phenotype and produce prodigious amounts of IL-9. A combination of large-scale proteomic analyses, lung intravital microscopy, and adoptive transfer of ILC9 cells revealed that high IL-9 expression distinguishes a multicytokine-producing state-of-activated ILC2s with an increased capacity to initiate IL-5-dependent allergic airway inflammation. Similar to IL-33 and TSLP, TL1A is expressed in airway basal cells in healthy and asthmatic human lungs. Together, these results indicate that TL1A is an epithelium-derived cytokine and an important cofactor of IL-33 in the airways.
{"title":"TL1A is an epithelial alarmin that cooperates with IL-33 for initiation of allergic airway inflammation.","authors":"Pauline Schmitt, Anais Duval, Mylène Camus, Emma Lefrançais, Stéphane Roga, Cécile Dedieu, Nathalie Ortega, Elisabeth Bellard, Emilie Mirey, Emmanuelle Mouton-Barbosa, Odile Burlet-Schiltz, Anne Gonzalez-de-Peredo, Corinne Cayrol, Jean-Philippe Girard","doi":"10.1084/jem.20231236","DOIUrl":"https://doi.org/10.1084/jem.20231236","url":null,"abstract":"<p><p>Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low \"ILC9\" phenotype and produce prodigious amounts of IL-9. A combination of large-scale proteomic analyses, lung intravital microscopy, and adoptive transfer of ILC9 cells revealed that high IL-9 expression distinguishes a multicytokine-producing state-of-activated ILC2s with an increased capacity to initiate IL-5-dependent allergic airway inflammation. Similar to IL-33 and TSLP, TL1A is expressed in airway basal cells in healthy and asthmatic human lungs. Together, these results indicate that TL1A is an epithelium-derived cytokine and an important cofactor of IL-33 in the airways.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11010340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855150","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 : 2024-06-03Epub Date: 2024-05-15DOI: 10.1084/jem.20240268
Matthias Eberl, Sheena M Cruickshank
The need to empower people to understand their health and well-being has never been greater. However, current research culture does not necessarily prioritize public involvement and engagement, and many scientists are left under-equipped to reap its benefits. Here, we outline both the positive need for purposeful public involvement and engagement in biomedical research and major systemic challenges. While some of our examples stem from the UK, we believe the learnings from them have global significance.
{"title":"A culture shift to support public involvement and engagement in research.","authors":"Matthias Eberl, Sheena M Cruickshank","doi":"10.1084/jem.20240268","DOIUrl":"10.1084/jem.20240268","url":null,"abstract":"<p><p>The need to empower people to understand their health and well-being has never been greater. However, current research culture does not necessarily prioritize public involvement and engagement, and many scientists are left under-equipped to reap its benefits. Here, we outline both the positive need for purposeful public involvement and engagement in biomedical research and major systemic challenges. While some of our examples stem from the UK, we believe the learnings from them have global significance.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11096847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921874","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 : 2024-05-06Epub Date: 2024-03-06DOI: 10.1084/jem.20231464
Alessia Baldo, Jeremy Di Domizio, Ahmad Yatim, Sophie Vandenberghe-Dürr, Raphael Jenelten, Anissa Fries, Lorenzo Grizzetti, François Kuonen, Carle Paul, Robert L Modlin, Curdin Conrad, Michel Gilliet
Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.
{"title":"Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26.","authors":"Alessia Baldo, Jeremy Di Domizio, Ahmad Yatim, Sophie Vandenberghe-Dürr, Raphael Jenelten, Anissa Fries, Lorenzo Grizzetti, François Kuonen, Carle Paul, Robert L Modlin, Curdin Conrad, Michel Gilliet","doi":"10.1084/jem.20231464","DOIUrl":"10.1084/jem.20231464","url":null,"abstract":"<p><p>Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049637","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}