{"title":"Linda-Gail Bekker: Mentorship is critical for anyone in STEM.","authors":"Lucie Van Emmenis","doi":"10.1084/jem.20240953","DOIUrl":"10.1084/jem.20240953","url":null,"abstract":"<p><p>Linda-Gail Bekker is a professor, chief executive officer of the Desmond Tutu HIV Foundation, and director of the Desmond Tutu HIV Centre at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. Her research interests include HIV treatment and prevention and tuberculosis, and she is active in developing community projects to promote education and research. We talked to Linda-Gail about her career, the importance of mentorship, and how rewarding it is to collaborate, mentor, and uplift other scientists.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419413","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}
Liangliang Wang, Connor Lynch, Sean P Pitroda, András Piffkó, Kaiting Yang, Amy K Huser, Hua Laura Liang, Ralph R Weichselbaum
{"title":"Radiotherapy and immunology.","authors":"Liangliang Wang, Connor Lynch, Sean P Pitroda, András Piffkó, Kaiting Yang, Amy K Huser, Hua Laura Liang, Ralph R Weichselbaum","doi":"10.1084/jem.20232101","DOIUrl":"10.1084/jem.20232101","url":null,"abstract":"<p><p>The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071076","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}
Yuexiao Tang, Tao Yao, Xin Tian, Xintong Xia, Xingxiao Huang, Zhewen Qin, Zhong Shen, Lin Zhao, Yaping Zhao, Bowen Diao, Yan Ping, Xiaoxiao Zheng, Yonghao Xu, Hui Chen, Tao Qian, Tao Ma, Ben Zhou, Suowen Xu, Qimin Zhou, Yong Liu, Mengle Shao, Wei Chen, Bo Shan, Ying Wu
{"title":"Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.","authors":"Yuexiao Tang, Tao Yao, Xin Tian, Xintong Xia, Xingxiao Huang, Zhewen Qin, Zhong Shen, Lin Zhao, Yaping Zhao, Bowen Diao, Yan Ping, Xiaoxiao Zheng, Yonghao Xu, Hui Chen, Tao Qian, Tao Ma, Ben Zhou, Suowen Xu, Qimin Zhou, Yong Liu, Mengle Shao, Wei Chen, Bo Shan, Ying Wu","doi":"10.1084/jem.20231395","DOIUrl":"10.1084/jem.20231395","url":null,"abstract":"<p><p>Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11070642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140862898","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}
{"title":"Csk restrains BCR-mediated ROS production and contributes to germinal center selection and affinity maturation.","authors":"Takeshi Inoue, Yuma Matsumoto, Chie Kawai, Mao Ito, Shigeyuki Nada, Masato Okada, Tomohiro Kurosaki","doi":"10.1084/jem.20231996","DOIUrl":"10.1084/jem.20231996","url":null,"abstract":"<p><p>Compared with naïve B cells, the B cell receptor (BCR) signal in germinal center (GC) B cells is attenuated; however, the significance of this signaling attenuation has not been well defined. Here, to investigate the role of attenuation of BCR signaling, we employed a Csk mutant mouse model in which Csk deficiency in GC B cells resulted in augmentation of net BCR signaling with no apparent effect on antigen presentation. We found that Csk is required for GC maintenance and efficient antibody affinity maturation. Mechanistically, ROS-induced apoptosis was exacerbated concomitantly with mitochondrial dysfunction in Csk-deficient GC B cells. Hence, our data suggest that attenuation of the BCR signal restrains hyper-ROS production, thereby protecting GC B cells from apoptosis and contributing to efficient affinity maturation.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11098938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944426","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}
{"title":"γδ T cells: The first line of defense for neonates.","authors":"Joshua I Gray, Donna L Farber","doi":"10.1084/jem.20240628","DOIUrl":"10.1084/jem.20240628","url":null,"abstract":"<p><p>A distinct CD83-expressing subset of γδ T cells are enriched in preterm infants with sepsis, providing insights into their functional maturation dynamics in settings of homeostasis and disease (León-Lara et al. https://doi.org/10.1084/jem.20231987).</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11143380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179758","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}
{"title":"TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition.","authors":"Yun Xue, Yuting Chen, Sijia Sun, Xinyuan Tong, Yujia Chen, Shijie Tang, Xue Wang, Simin Bi, Yuqin Qiu, Qiqi Zhao, Zhen Qin, Qin Xu, Yingjie Ai, Leilei Chen, Beizhen Zhang, Zhijie Liu, Minbiao Ji, Meidong Lang, Luonan Chen, Guoliang Xu, Liang Hu, Dan Ye, Hongbin Ji","doi":"10.1084/jem.20240111","DOIUrl":"10.1084/jem.20240111","url":null,"abstract":"<p><p>Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158359","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}
Ian S Cohn, Bethan A Wallbank, Breanne E Haskins, Keenan M O'Dea, Ryan D Pardy, Sebastian Shaw, Maria I Merolle, Jodi A Gullicksrud, David A Christian, Boris Striepen, Christopher A Hunter
{"title":"Intestinal cDC1s provide cues required for CD4+ T cell-mediated resistance to Cryptosporidium.","authors":"Ian S Cohn, Bethan A Wallbank, Breanne E Haskins, Keenan M O'Dea, Ryan D Pardy, Sebastian Shaw, Maria I Merolle, Jodi A Gullicksrud, David A Christian, Boris Striepen, Christopher A Hunter","doi":"10.1084/jem.20232067","DOIUrl":"10.1084/jem.20232067","url":null,"abstract":"<p><p>Cryptosporidium is an enteric pathogen and a prominent cause of diarrheal disease worldwide. Control of Cryptosporidium requires CD4+ T cells, but how protective CD4+ T cell responses are generated is poorly understood. Here, Cryptosporidium parasites that express MHCII-restricted model antigens were generated to understand the basis for CD4+ T cell priming and effector function. These studies revealed that parasite-specific CD4+ T cells are primed in the draining mesenteric lymph node but differentiate into Th1 cells in the gut to provide local parasite control. Although type 1 conventional dendritic cells (cDC1s) were dispensable for CD4+ T cell priming, they were required for CD4+ T cell gut homing and were a source of IL-12 at the site of infection that promoted local production of IFN-γ. Thus, cDC1s have distinct roles in shaping CD4+ T cell responses to an enteric infection: first, to promote gut homing from the mesLN, and second, to drive effector responses in the intestine.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199483","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}
Andrew J MacLean, Joao P P L Bonifacio, Sophia L Oram, Mona O Mohsen, Martin F Bachmann, Tal I Arnon
{"title":"Regulation of pulmonary plasma cell responses during secondary infection with influenza virus.","authors":"Andrew J MacLean, Joao P P L Bonifacio, Sophia L Oram, Mona O Mohsen, Martin F Bachmann, Tal I Arnon","doi":"10.1084/jem.20232014","DOIUrl":"https://doi.org/10.1084/jem.20232014","url":null,"abstract":"<p><p>During secondary infection with influenza virus, plasma cells (PCs) develop within the lung, providing a local source of antibodies. However, the site and mechanisms that regulate this process are poorly defined. Here, we show that while circulating memory B cells entered the lung during rechallenge and were activated within inducible bronchus-associated lymphoid tissues (iBALTs), resident memory B (BRM) cells responded earlier, and their activation occurred in a different niche: directly near infected alveoli. This process required NK cells but was largely independent of CD4 and CD8 T cells. Innate stimuli induced by virus-like particles containing ssRNA triggered BRM cell differentiation in the absence of cognate antigen, suggesting a low threshold of activation. In contrast, expansion of PCs in iBALTs took longer to develop and was critically dependent on CD4 T cells. Our work demonstrates that spatially distinct mechanisms evolved to support pulmonary secondary PC responses, and it reveals a specialized function for BRM cells as guardians of the alveoli.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11044945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865361","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}
Tamara Kögl, Hsin-Fang Chang, Julian Staniek, Samuel C C Chiang, Gudrun Thoulass, Jessica Lao, Kristoffer Weißert, Viviane Dettmer-Monaco, Kerstin Geiger, Paul T Manna, Vivien Beziat, Mana Momenilandi, Szu-Min Tu, Selina J Keppler, Varsha Pattu, Philipp Wolf, Laurence Kupferschmid, Stefan Tholen, Laura E Covill, Karolina Ebert, Tobias Straub, Miriam Groß, Ruth Gather, Helena Engel, Ulrich Salzer, Christoph Schell, Sarah Maier, Kai Lehmberg, Tatjana I Cornu, Hanspeter Pircher, Mohammad Shahrooei, Nima Parvaneh, Roland Elling, Marta Rizzi, Yenan T Bryceson, Stephan Ehl, Peter Aichele, Sandra Ammann
{"title":"Correction: Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.","authors":"Tamara Kögl, Hsin-Fang Chang, Julian Staniek, Samuel C C Chiang, Gudrun Thoulass, Jessica Lao, Kristoffer Weißert, Viviane Dettmer-Monaco, Kerstin Geiger, Paul T Manna, Vivien Beziat, Mana Momenilandi, Szu-Min Tu, Selina J Keppler, Varsha Pattu, Philipp Wolf, Laurence Kupferschmid, Stefan Tholen, Laura E Covill, Karolina Ebert, Tobias Straub, Miriam Groß, Ruth Gather, Helena Engel, Ulrich Salzer, Christoph Schell, Sarah Maier, Kai Lehmberg, Tatjana I Cornu, Hanspeter Pircher, Mohammad Shahrooei, Nima Parvaneh, Roland Elling, Marta Rizzi, Yenan T Bryceson, Stephan Ehl, Peter Aichele, Sandra Ammann","doi":"10.1084/jem.2022112205142024c","DOIUrl":"10.1084/jem.2022112205142024c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 7","pages":""},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071075","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}
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
{"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":"221 6","pages":""},"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}
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