Nature Immunology最新文献

{"title":"Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE","authors":"Caterina E. Faliti, Trinh T. P. Van, Fabliha A. Anam, Narayanaiah Cheedarla, M. Elliott Williams, Ashish Kumar Mishra, Sabeena Y. Usman, Matthew C. Woodruff, Geoff Kraker, Martin C. Runnstrom, Shuya Kyu, Daniel Sanz, Hasan Ahmed, Midushi Ghimire, Andrea Morrison-Porter, Hannah Quehl, Natalie S. Haddad, Weirong Chen, Suneethamma Cheedarla, Andrew S. Neish, John D. Roback, Rustom Antia, Jennifer Hom, Christopher M. Tipton, John M. Lindner, Eliver Ghosn, Surender Khurana, Christopher D. Scharer, Arezou Khosroshahi, F. Eun-Hyung Lee, Ignacio Sanz","doi":"10.1038/s41590-024-02010-9","DOIUrl":"10.1038/s41590-024-02010-9","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD−CD27− ‘double-negative (DN)’ DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells. SLE is a heterogeneous disorder that is characterized by different immune endotypes. Faliti et al. follow the immune memory responses upon mRNA COVID-19 vaccinations in a large cohort of patients with SLE. They note that skewed immune responses, such as lower seroconversion and neutralization, might be due to extrafollicular B and T cell biases in SLE endotypes.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 1","pages":"131-145"},"PeriodicalIF":27.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-02010-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599626","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":"Immune drivers of pain resolution and protection","authors":"Sara Hakim, Aakanksha Jain, Clifford J. Woolf","doi":"10.1038/s41590-024-02002-9","DOIUrl":"10.1038/s41590-024-02002-9","url":null,"abstract":"Immune cells are involved in the pathogenesis of pain by directly activating or sensitizing nociceptor sensory neurons. However, because the immune system also has the capacity to self-regulate through anti-inflammatory mechanisms that drive the resolution of inflammation, it might promote pain resolution and prevention. Here, we describe how immune cell-derived cytokines can act directly on sensory neurons to inhibit pain hypersensitivity and how immune-derived endogenous opioids promote analgesia. We also discuss how immune cells support healthy tissue innervation by clearing debris after nerve injury, protecting against axon retraction from target tissues and enhancing regeneration, preventing the development of chronic neuropathic pain. Finally, we review the accumulating evidence that manipulating immune activity positively alters somatosensation, albeit with currently unclear molecular and cellular mechanisms. Exploration of immune-mediated analgesia and pain prevention could, therefore, be important for the development of novel immune therapies for the treatment of clinical pain states. Woolf and colleagues review the current evidence that immune cells could promote pain resolution and prevention through direct effects on sensory neurons and through maintaining healthy tissue innervation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2200-2208"},"PeriodicalIF":27.7,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598038","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}

{"title":"Lactate fermentation intoxicates TILs","authors":"Brian G. Hunt, Emily Kessler, Nikhil S. Joshi","doi":"10.1038/s41590-024-02020-7","DOIUrl":"10.1038/s41590-024-02020-7","url":null,"abstract":"Tumor-infiltrating T cells are known to encounter chronic antigens and hypoxia, which results in exhaustion and dysfunction. New data show that lactate fermentation, a characteristic of solid tumors, promotes the uptake of lactate into T cells via the monocarboxylate transporter MCT11, which reduces the metabolic fitness and anti-tumor function of these cells, an effect that might be targeted by immunotherapy.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2176-2177"},"PeriodicalIF":27.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596854","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}

{"title":"Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism","authors":"Ronal M. Peralta, Bingxian Xie, Konstantinos Lontos, Hector Nieves-Rosado, Kellie Spahr, Supriya Joshi, B. Rhodes Ford, Kevin Quann, Andrew T. Frisch, Victoria Dean, Mary Philbin, Anthony R. Cillo, Sebastian Gingras, Amanda C. Poholek, Lawrence P. Kane, Dayana B. Rivadeneira, Greg M. Delgoffe","doi":"10.1038/s41590-024-01999-3","DOIUrl":"10.1038/s41590-024-01999-3","url":null,"abstract":"CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally Tex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which Tex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME. Here the authors show that high expression of MCT11 is key to the dysfunctionality associated with exhausted CD8+ T cells in tumors. By targeting MCT11, uptake of lactic acid, which is abundant in the tumor, is reduced, resulting in improved effector functions and tumor immunity.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2297-2307"},"PeriodicalIF":27.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01999-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596855","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":"Nanotech unveils cytokine traces in post-COVID cardiovascular complications","authors":"Harish Narasimhan, Jie Sun","doi":"10.1038/s41590-024-02017-2","DOIUrl":"10.1038/s41590-024-02017-2","url":null,"abstract":"Trace levels of circulating cytokines correlate with the prevalence of cardiovascular symptoms following COVID-19.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2178-2179"},"PeriodicalIF":27.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596853","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}

{"title":"Inborn errors of immunity caused by dominant negative interference by a BCL11B variant","authors":"","doi":"10.1038/s41590-024-02003-8","DOIUrl":"10.1038/s41590-024-02003-8","url":null,"abstract":"We generated a mouse model to investigate the mechanistic basis of inborn errors of immunity caused by heterozygous BCL11B mutation. The BCL11B mutant protein interfered with BCL11A function, impairing T cell and neuronal development. Mutant BCL11B also failed to antagonize TCF1 function, leading to aberrant natural killer cell differentiation in the thymus.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2184-2185"},"PeriodicalIF":27.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588688","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}

{"title":"Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease","authors":"Emma C. Walker, Sarah Javati, Elizabeth M. Todd, John-Paul Matlam, Xue Lin, Michelle Bryant, Emily Krone, Rashmi Ramani, Pallavi Chandra, Taylor P. Green, Edgar P. Anaya, Julie Y. Zhou, Katherine A. Alexander, R. Spencer Tong, Lapule Yuasi, Sebastian Boluarte, Fan Yang, Lina Greenberg, Jeanne M. Nerbonne, Michael J. Greenberg, Regina A. Clemens, Jennifer A. Philips, Leslie D. Wilson, Carmen M. Halabi, Brian J. DeBosch, Christopher C. Blyth, Todd E. Druley, James W. Kazura, William S. Pomat, Sharon Celeste Morley","doi":"10.1038/s41590-024-01998-4","DOIUrl":"10.1038/s41590-024-01998-4","url":null,"abstract":"Acute lower respiratory tract infection (ALRI) remains a major worldwide cause of childhood mortality, compelling innovation in prevention and treatment. Children in Papua New Guinea (PNG) experience profound morbidity from ALRI caused by Streptococcus pneumoniae. As a result of evolutionary divergence, the human PNG population exhibits profound genetic variation and diversity. To address unmet health needs of children in PNG, we tested whether genetic variants increased ALRI morbidity. Whole-exome sequencing of a pilot child cohort identified homozygosity for a novel single-nucleotide variant (SNV) in coenzyme Q6 (COQ6) in cases with ALRI. COQ6 encodes a mitochondrial enzyme essential for biosynthesis of ubiquinone, an electron acceptor in the electron transport chain. A significant association of SNV homozygosity with ALRI was replicated in an independent ALRI cohort (P = 0.036). Mice homozygous for homologous mouse variant Coq6 exhibited increased mortality after pneumococcal lung infection, confirming causality. Bone marrow chimeric mice further revealed that expression of variant Coq6 in recipient (that is, nonhematopoietic) tissues conferred increased mortality. Variant Coq6 maintained ubiquinone biosynthesis, while accelerating metabolic remodeling after pneumococcal challenge. Identification of this COQ6 variant provides a genetic basis for increased pneumonia susceptibility in PNG and establishes a previously unrecognized role for the enzyme COQ6 in regulating inflammatory-mediated metabolic remodeling. Morley, Pomat and colleagues identify a homozygous mutation in COQ6 in an indigenous population of Papua New Guinea. This allele predisposes children to increased risk of acute lower respiratory infections in response to Streptococcus pneumoniae. This sensitivity is recapitulated in Coq6DY mice in the nonhematopoietic compartment.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2247-2258"},"PeriodicalIF":27.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574514","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}

{"title":"COQ6 defies immune and metabolic expectations","authors":"Samuel E. Weinberg, Navdeep S. Chandel","doi":"10.1038/s41590-024-02005-6","DOIUrl":"10.1038/s41590-024-02005-6","url":null,"abstract":"A COQ6 variant increases susceptibility to pneumococcal infection via non-bone marrow-derived cells without affecting ubiquinone synthesis, challenging traditional views on the metabolic role of COQ6 role and opening new avenues for understanding immunometabolic interactions.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2170-2172"},"PeriodicalIF":27.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574507","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}

{"title":"Post-translational control of B lineage commitment","authors":"Junli Nie, Ashley P. Ng, Stephen L. Nutt","doi":"10.1038/s41590-024-02019-0","DOIUrl":"10.1038/s41590-024-02019-0","url":null,"abstract":"PAX5 controls the gene regulatory circuit that leads to B cell lineage commitment. A detailed study shows that the stability of PAX5 protein is reduced by acetylation, and that SIRT7-dependent deacetylation is required for full PAX5 activity.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2173-2175"},"PeriodicalIF":27.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562147","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}

{"title":"A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development","authors":"Kazuki Okuyama, Motoi Yamashita, Artemis Koumoundourou, Christoph Wiegreffe, Michiko Ohno-Oishi, Samuel J. H. Murphy, Xin Zhao, Hideyuki Yoshida, Takashi Ebihara, Naoko Satoh-Takayama, Satoshi Kojo, Hiroshi Ohno, Tomohiro Morio, Yibo Wu, Jennifer Puck, Hai-Hui Xue, Stefan Britsch, Ichiro Taniuchi","doi":"10.1038/s41590-024-01997-5","DOIUrl":"10.1038/s41590-024-01997-5","url":null,"abstract":"Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11BN441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11bN440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46+ cells in the thymus and reduction in TBR1+ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11bN440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins. Taniuchi and colleagues describe the generation and phenotype of a mouse model carrying a defective Bcl11b allele encoding a mutant protein corresponding to BCL11B-N441K previously associated with human disease. They further characterize the molecular interactions between the mutant BCL11B protein and other transcription factors involved in early thymocyte development.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2284-2296"},"PeriodicalIF":27.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562149","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}