Journal of immunology最新文献_第9页

Lowering CD40L expression in murine lupus results in an increase in disease indicators in female but not male B6 mice. 小鼠狼疮中CD40L表达的降低导致雌性B6小鼠疾病指标的增加，而雄性B6小鼠则没有。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag205

Diego Prado De Maio, Sandra Tetteh, Christopher Ayers, Anna St Martin, Michelle Brown, Lori R Covey

{"title":"Lowering CD40L expression in murine lupus results in an increase in disease indicators in female but not male B6 mice.","authors":"Diego Prado De Maio, Sandra Tetteh, Christopher Ayers, Anna St Martin, Michelle Brown, Lori R Covey","doi":"10.1093/jimmun/vkag205","DOIUrl":"10.1093/jimmun/vkag205","url":null,"abstract":"Our laboratory has previously described a mouse model (CD40LΔ5) that produces 60% of wild-type CD40L due to a targeted deletion in an RNA binding site within the CD40L message. The CD40LΔ5 mutation, which destabilizes CD40L mRNA during T-cell activation, causes disrupted germinal center (GC) formation, leading to reduced levels of memory B cells and switched antibodies. In this study, we used our model of limited CD40L expression to investigate its effect on systemic lupus erythematosus (SLE, or lupus) using 2 different mouse models of SLE. The first model used the hydrocarbon oil pristane to induce lupus-like symptoms over a 6-month period, and the second utilized a chronic graft-versus-host disease (bm12-cGVHD) that resembles lupus and allowed us to monitor the early events in disease development. Importantly, we found that in both systems, female mice expressing the CD40LΔ5 mutation showed a consistent increase in elevated antibody-secreting cells and autoantibody titers. In addition, pristane-induced lupus female CD40LΔ5 mice had higher levels of immunocomplex deposition in the kidney compared to all other cohorts. Increases in autoantibodies and GC cells in female CD40LΔ5 versus wild-type recipient mice were also evident in the bm12-cGVHD model. Additionally, CD4+ T cells from female CD40LΔ5 recipient mice were skewed toward a Th2 phenotype and expressed a distinct cytokine expression pattern upon activation of dendritic cells. Overall, our results support a nuanced role for optimal CD40L expression in lupus and suggest a sex-determined threshold of CD40L-CD40 signaling that is critical at the very early steps of disease progression.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13420501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-term survivors of melanoma after anti-PD-1 therapy demonstrate on-treatment increase in abundance of 4-1BB+ CD4 T cells in blood. 抗pd -1治疗后黑色素瘤的长期幸存者显示治疗期间血液中4-1BB+ CD4 T细胞的丰度增加。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag171

Karlijn de Joode, Hayri E Balcioglu, Mandy van Brakel, María T López-Cascales, Daan P Hurkmans, Edwin A Basak, Esther Oomen-de Hoop, Cor H Lamers, Joachim G Aerts, Ron H Mathijssen, Astrid A M van der Veldt, Reno Debets

{"title":"Long-term survivors of melanoma after anti-PD-1 therapy demonstrate on-treatment increase in abundance of 4-1BB+ CD4 T cells in blood.","authors":"Karlijn de Joode, Hayri E Balcioglu, Mandy van Brakel, María T López-Cascales, Daan P Hurkmans, Edwin A Basak, Esther Oomen-de Hoop, Cor H Lamers, Joachim G Aerts, Ron H Mathijssen, Astrid A M van der Veldt, Reno Debets","doi":"10.1093/jimmun/vkag171","DOIUrl":"https://doi.org/10.1093/jimmun/vkag171","url":null,"abstract":"Anti-PD-1 monotherapy has shown a significant survival benefit for patients with advanced-stage melanoma. In this study, we explored whether long-term clinical benefit is determined by abundance or changes in such abundances of CD4 and CD8 T-cell subsets in blood. Peripheral blood mononuclear cells from 58 patients with advanced-stage melanoma treated with anti-PD-1 monotherapy were collected prior to first, second, and third administration. Overall survival (OS) was categorized into 3 groups: <1 yr (short term); 1-3 yr; and >3 yr (long term). The abundance of different T-cell subsets was determined via multiplex flow cytometry and transcriptomics analysis. Long- and short-term survivors demonstrated no differences in frequencies of CD4 and CD8 T-cell subsets at baseline. However, on-treatment, long-term survivors showed an early increase in the frequency of CD4 T cells expressing 4-1BB, whereas this subset frequency was decreased in short-term survivors. Notably, this early increase in the 4-1BB+ CD4 T-cell frequency was associated with an increase in the frequency of LAG3+TIM3+ CD4 T cells and followed by a later decrease in the frequency of FOXP3+ CD4 T cells. Notably, 4-1BB+ CD4 T cells of long-term survivors demonstrated a distinctively high expression of IL-17. In short, long-term survivors have unique on-treatment changes in the frequency of different CD4 T-cell subsets, particularly those related to co-signaling and regulatory T cells. These results show that CD4 T cell-mediated stimulation and differentiation are associated with long-term benefit of anti-PD-1 treatment, which may guide development of future treatment strategies.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148421660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hidden effects of polymyxin B: Its role in activating TLR2-mediated inflammatory responses. 多粘菌素B在激活tlr2介导的炎症反应中的作用

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag193

Yoshikuni Goto, Yuko Ogawa, Kenji Ogawa, Atsushi Ohnishi, Kazuma Aoki, Takahiro J Nakamura, Masayuki Nakanishi

{"title":"Hidden effects of polymyxin B: Its role in activating TLR2-mediated inflammatory responses.","authors":"Yoshikuni Goto, Yuko Ogawa, Kenji Ogawa, Atsushi Ohnishi, Kazuma Aoki, Takahiro J Nakamura, Masayuki Nakanishi","doi":"10.1093/jimmun/vkag193","DOIUrl":"https://doi.org/10.1093/jimmun/vkag193","url":null,"abstract":"Polymyxins are cyclic cationic lipopeptide antibiotics that disrupt both the outer and inner membranes of Gram-negative bacteria. They also bind to bacterial lipopolysaccharides (LPSs), thereby inhibiting LPS recognition by Toll-like receptor 4 (TLR4) and preventing macrophage activation. However, the immunomodulatory effects of polymyxin B during infection, in which multiple host- and bacteria-derived factors coexist, remain unclear. In this study, we examined the impact of polymyxin B, a representative polymyxin antibiotic, on mouse macrophage responses in the presence of interferon γ (IFN-γ), with or without LPS stimulation. Polymyxin B induced nitric oxide (NO) production when macrophages were exposed to high concentrations of IFN-γ. In the presence of lower concentrations of IFN-γ, polymyxin B alone cannot induce NO production, but together with LPS can cause the induction of NO production. These NO productions were not largely affected by TLR4 deficiency but were attenuated when TLR2 was deficient. Furthermore, polymyxin B-immobilized agarose beads precipitated TLR2 from cell extracts, indicating an association between polymyxin B and TLR2. This association was not inhibited by LPS, although polymyxin B and LPS synergistically induced NO production. Collectively, these findings demonstrate that polymyxin B (together with LPS) associates with TLR2 and functions as a TLR2 agonist, suggesting that polymyxin B preparations can induce macrophage activation under conditions in which IFN-γ and LPS are present.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distinct kinetic features of innate and adaptive responses in influenza A versus influenza B-infected mice. 甲型流感和乙型流感感染小鼠先天和适应性反应的不同动力学特征。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag196

Sean A Nelson, Ajitanuj Rattan, Bindumadhav Marathe, Chantelle L White, Max C Eismann, Katherine A Richards, Richard J Webby, Andrea J Sant

{"title":"Distinct kinetic features of innate and adaptive responses in influenza A versus influenza B-infected mice.","authors":"Sean A Nelson, Ajitanuj Rattan, Bindumadhav Marathe, Chantelle L White, Max C Eismann, Katherine A Richards, Richard J Webby, Andrea J Sant","doi":"10.1093/jimmun/vkag196","DOIUrl":"10.1093/jimmun/vkag196","url":null,"abstract":"Influenza B infection is an important source of morbidity and mortality, especially in vulnerable populations such as children. Improved vaccines and antiviral therapeutics are hindered by gaps in knowledge about influenza B viruses (IBVs). We examined the immune responses in the lung, at the kinetic interface between the innate and adaptive response with a focus on the CD4 T-cell response to infection. Using a mouse model of infection with influenza A virus (IAV) A/California/04/2009 and influenza B virus (IBV) B/Brisbane/60/2008, striking differences in early cytokines and chemokines associated with induction of Th1-biased immune responses were identified. Quantifying these mediators on a temporal basis, IBV infection leads to earlier lung expression of the cytokines IFN-γ, IP-10, and MIP1-B in the lung relative to IAV. Given the critical role for IFN-γ in antiviral responses, the use of direct ex vivo cytokine staining and multiparameter flow cytometry revealed that, at day 6 after infection, when lung lysates contained the highest levels of IFN-γ, significant differences were found in the abundance of IFN-γ-producing Ly6C+ monocytes, CD4 T cells, and CD8 T cells in the IBV-infected lung, but not the IAV-infected lung. Data from a reporter mouse model of T-cell receptor engagement, epitope-specific cytokine enzyme-linked immunospot assays, quantitative lung cytokine abundance, and earlier viral clearance suggest a distinctive mechanism of IBV and IAV responses whereby the kinetics in recruitment of epitope-specific T cells to the IBV-infected lung is driven by early innate responses and leads to more rapid viral clearance.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148603812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fluorescence tracking CD8 T cells from tumor-draining lymph nodes to irradiated tumors and their activation in the tumor environment. 荧光跟踪CD8 T细胞从肿瘤引流淋巴结到辐照肿瘤及其在肿瘤环境中的激活。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag142

David Friedman, Gwen Kramer, Alejandro F Alice, Jason Baird, Sina Ramin, Terry Medler, Kristina H Young, Madeleine G Kaiser, Clemens Grassberger, Marka R Crittenden, Michael J Gough

{"title":"Fluorescence tracking CD8 T cells from tumor-draining lymph nodes to irradiated tumors and their activation in the tumor environment.","authors":"David Friedman, Gwen Kramer, Alejandro F Alice, Jason Baird, Sina Ramin, Terry Medler, Kristina H Young, Madeleine G Kaiser, Clemens Grassberger, Marka R Crittenden, Michael J Gough","doi":"10.1093/jimmun/vkag142","DOIUrl":"10.1093/jimmun/vkag142","url":null,"abstract":"Radiation is an effective site-specific cytotoxic therapy for cancer cells. In preclinical models, CD8 T cells are essential for optimum tumor control by radiation therapy, yet CD8 T cells are radiosensitive and depleted within the treatment field. Irradiated tumors can be refilled with T cells that were outside the field at the time of treatment. Using the Kaede photoconvertible mouse model we tracked CD8 T cells that originated in the tumor-draining lymph node and entered the tumor following radiation therapy. We show that radiation induces CD69 expression in newly infiltrating CD8 T cells within the tumor; however, this activation is not antigen-specific activation, but rather ois mediated by type I interferon released following radiation therapy. This effect is radiation dose dependent and requires cGAS expression in the cancer cells. Mathematical modeling demonstrates that radiation results in increased retention of surviving CD8 T cells in the tumor environment following treatment. By tracking the movement of tumor antigen-specific CD8 T cells from the tumor-draining lymph node to the tumor, we can observe that these cells rapidly express exhaustion markers in the tumor environment. These events occur in advance of radiation-mediated antigen-specific T cell expansion in the tumor-draining lymph node. These data formally demonstrate movement of CD8 T cells from the tumor-draining lymph node to the irradiated tumor and identify a mechanism of innate inflammation-mediated T cell activation that may impact T cell retention and accelerates refilling of the irradiated tumor.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13378428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A mutation in PTPN6 associated to emphysema alters B-lymphocyte biology in humans and mice. 与肺气肿相关的PTPN6突变改变了人类和小鼠的b淋巴细胞生物学。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag162

Marie Pineault, Nadia Milad, Gabrielle Bouffard, Félix Tremblay, Joanie Routhier, Marie-Josée Beaulieu, Sophie Aubin, Ariane Lechasseur, Yohan Bossé, François Maltais, Mathieu C Morissette

{"title":"A mutation in PTPN6 associated to emphysema alters B-lymphocyte biology in humans and mice.","authors":"Marie Pineault, Nadia Milad, Gabrielle Bouffard, Félix Tremblay, Joanie Routhier, Marie-Josée Beaulieu, Sophie Aubin, Ariane Lechasseur, Yohan Bossé, François Maltais, Mathieu C Morissette","doi":"10.1093/jimmun/vkag162","DOIUrl":"10.1093/jimmun/vkag162","url":null,"abstract":"Our group discovered a mutation in a French-Canadian family causing a severe and early-onset form of emphysema. The heterozygote mutation located in the PTPN6 gene causes an alanine to threonine switch near the catalytic site of SHP-1, leading to a reduction of its enzymatic activity. In this study, we aimed to characterize the respiratory and immune abnormalities caused by this mutation in human carriers (PTPN6Ala455Thr) and mice carrying the equivalent mutation (Ptpn6Ala457Thr/+). Ptpn6Ala457Thr/+ mice spontaneously developed pulmonary tertiary lymphoid tissues (TLTs). They also exhibited a higher proportion of B-1 cells in both lung and spleen. Ptpn6Ala457Thr/+ mice had lower IgG1-specific antibodies to T-independent immunization, while their T-dependent response was normal. Human carriers showed reduced circulating naive B lymphocytes and increased memory B lymphocytes, a phenotype mainly observed in men, and had lower circulating levels of IgG1 and IgG4 as well as higher levels of IgG3. Spontaneous TLT formation in mice and alterations of B-cell biology in both humans and mice are caused by the mutation. This reinforces the link between emphysema, pulmonary TLT formation, and B cells; however, the exact mechanism involving B cells and pulmonary TLT in the development of emphysema remains elusive.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13349814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148421668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Immunosuppressive effects of voclosporin in inflammatory bowel disease through targeted inhibition of SLP-76 and metabolic reprogramming. 通过靶向抑制SLP-76和代谢重编程对炎症性肠病的免疫抑制作用

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag175

Laura Loges, Michael Gabel, Annkathrin Knauss, Raja Atreya, Arne Gessner, Nora Bartels, Markus F Neurath, Benno Weigmann

{"title":"Immunosuppressive effects of voclosporin in inflammatory bowel disease through targeted inhibition of SLP-76 and metabolic reprogramming.","authors":"Laura Loges, Michael Gabel, Annkathrin Knauss, Raja Atreya, Arne Gessner, Nora Bartels, Markus F Neurath, Benno Weigmann","doi":"10.1093/jimmun/vkag175","DOIUrl":"https://doi.org/10.1093/jimmun/vkag175","url":null,"abstract":"The adaptor protein SLP-76 plays a critical role in T-cell receptor signaling and immune activation, yet its relevance in inflammatory bowel disease (IBD) remains unclear. Although calcineurin inhibitors such as cyclosporine A (CsA) are used in severe ulcerative colitis, voclosporin (VCS), a novel calcineurin inhibitor approved for lupus nephritis, has not been systematically evaluated in IBD. We investigated whether SLP-76 is dysregulated in IBD and can be modulated by calcineurin inhibitors. Expression of SLP-76 was analyzed in intestinal biopsy specimens of patients with ulcerative colitis and Crohn's disease using quantitative PCR (qPCR) and immunofluorescence. PBMCs from patients with IBD and healthy control participants were stimulated with anti-CD3/CD28 in the presence or absence of CsA or VCS. Downstream effects were analyzed by qPCR, flow cytometry, cytokine, and metabolic profiling. SLP-76 was significantly upregulated in inflamed intestinal tissue and correlated significantly with histological inflammation. No differences were observed in PBMCs between control participants and patients with IBD. Both calcineurin inhibitors reduced phosphorylation of SLP-76 and impaired downstream signaling in CD4+ and CD8+ T cells. However, only VCS significantly decreased total SLP-76 protein and suppressed expression of the early activation marker CD69 and Ras-MAPL signaling. Metabolomic profiling showed that VCS induced distinct metabolic changes compared with CsA. Our findings highlight SLP-76 as a potential immunoregulatory target in IBD and suggest that VCS exerts broader immunosuppressive effects than CsA, supporting its repurposing as a therapeutic strategy.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The transcription factor SREBP2 supports the activation and homeostasis of CD4+ Foxp3+ regulatory T cells. 转录因子SREBP2支持CD4+ Foxp3+调节性T细胞的激活和稳态。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag181

Acacia N Shouse, Alejandro V Villarino, Thomas R Malek

{"title":"The transcription factor SREBP2 supports the activation and homeostasis of CD4+ Foxp3+ regulatory T cells.","authors":"Acacia N Shouse, Alejandro V Villarino, Thomas R Malek","doi":"10.1093/jimmun/vkag181","DOIUrl":"10.1093/jimmun/vkag181","url":null,"abstract":"Periodic activation of regulatory T cells (Tregs) is necessary to restrict autoreactive T cells and maintain immune homeostasis. IL-2-STAT5 signaling instructs several metabolic processes underlying Treg activation, including the mevalonate pathway, which is crucial for optimal Treg responses. However, direct links between IL-2-STAT5, mevalonate, and Treg function have yet to be established. To explore this relationship, we deleted sterol regulatory binding element protein 2 (Srebp2), a critical mediator of mevalonate metabolism, selectively in Tregs. Here, we show that when Srebp2-deficient Tregs are placed under physiological stress by competing with wild-type Tregs, the former exhibit impaired proliferation, survival, and activation. RNA sequencing of Tregs in this competitive setting demonstrate that Srebp2 contributes to pathways controlling IL-2R signaling, cholesterol homeostasis, activities associated with the mevalonate pathway, and expression of genes associated with activated Tregs. These findings link Srebp2, the IL-2R, and the mevalonate pathways for efficient Treg homeostasis and activation. These effects, however, require a competitive setting, as mice with only Srebp2-deficient Tregs were outwardly normal with respect to their development, homeostasis, metabolic activity, and function. Thus, Srebp2 is necessary to optimally tune Treg homeostasis and activation, but sufficient redundancy exists to compensate for the lack of Srebp2 to maintain Treg development and function in the absence of physiological stress.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13378427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phylogenetic analysis of amino acid sequences indicates a central role of transmembrane domain structural elements in MHC class II function. 氨基酸序列的系统发育分析表明跨膜结构域元件在MHC II类功能中起中心作用。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag192

Konstantina Karathanou, Jamie L Duke, Sophia M Cangialosi, Luke Marlow, Ann M Dixon, Dimitri S Monos, James R Drake

{"title":"Phylogenetic analysis of amino acid sequences indicates a central role of transmembrane domain structural elements in MHC class II function.","authors":"Konstantina Karathanou, Jamie L Duke, Sophia M Cangialosi, Luke Marlow, Ann M Dixon, Dimitri S Monos, James R Drake","doi":"10.1093/jimmun/vkag192","DOIUrl":"10.1093/jimmun/vkag192","url":null,"abstract":"Human leukocyte antigen class II genes are highly polymorphic. This raises the question of how polymorphisms are distributed across the entirety of the class II molecule and how this distribution affects function. We performed a comprehensive analysis of amino acid variability across the entire class II molecule, using class II amino acid sequences ranging from humans to ancient species such as cartilaginous fish. This analysis is unique in its scale and reveals that while the membrane distal antigen recognition domain exhibits a high frequency of amino acid variability, other domains exhibit much lower degrees of variability. Notably, the transmembrane domain (TMD) exhibits the lowest amino acid variability, consistent with its role in driving core class II functions. Further analysis of the TMD revealed that a cysteine residue and 3 GxxxG (GG4) motifs are 100% conserved throughout evolution. Mutagenesis and monoclonal antibody binding studies revealed that both the GG4 motifs and cysteine residue (the latter a site of class II palmitoylation) are involved in conformer formation. Molecular dynamics simulation of the palmitoylated class II TMD provides a framework for understanding the contribution of GG4 motif pairing and cysteine palmitoylation to class II structure. These results reveal a domain-specific organization of polymorphism within class II and a key role for the TMD and its functional residues/motifs in major histocompatibility complex class II immunobiology.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13399432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Systemic and lung-resident memory elicited by OC43 coronavirus infection in mice. OC43冠状病毒感染引发小鼠全身和肺驻留记忆。

IF 4 3区医学

Journal of immunology Pub Date : 2026-07-10 DOI: 10.1093/jimmun/vkag182

Nathan L Sanders, Devin Kenney, Neelou S Etesami, Anukul T Shenoy, Konstantinos Kontodimas, Julian Amirault, Chioma Okolo, Viviana A Dominguez, Marc Semaan, Ekaterina Murzin, James A Lederer, Florian Douam, Mohsan Saeed, Joseph P Mizgerd

{"title":"Systemic and lung-resident memory elicited by OC43 coronavirus infection in mice.","authors":"Nathan L Sanders, Devin Kenney, Neelou S Etesami, Anukul T Shenoy, Konstantinos Kontodimas, Julian Amirault, Chioma Okolo, Viviana A Dominguez, Marc Semaan, Ekaterina Murzin, James A Lederer, Florian Douam, Mohsan Saeed, Joseph P Mizgerd","doi":"10.1093/jimmun/vkag182","DOIUrl":"https://doi.org/10.1093/jimmun/vkag182","url":null,"abstract":"Endemic coronaviruses circulate seasonally and, while typically mild, can produce robust inflammation and severe pneumonia. Immunological memory to coronaviruses can be cross-reactive for multiple coronaviruses including OC43 and SARS-CoV-2. In this study, we used mouse models to investigate immune responses elicited by pulmonary infection with OC43. OC43 caused a mild, self-limiting infection. Early after infection, there was acute influx of myeloid cells and lymphocytes to the lung as well as a type I interferon-dependent production of IFN-γ. However, blocking interferons did not enhance viral infection. After recovery, lungs contained resident memory lymphocytes, and both the blood and lungs contained antibodies against OC43. When infection was supplemented with proinflammatory stimuli to model more severe disease, OC43-elicited immune changes were bolstered, including increased virus-specific plasma IgG and lung IgA, enhanced lung B-cell class-switching, and increased antigen-specific Th1 and Th17 cytokine production from lung CD4+ T cells. The antibodies and CD4+ T cells in mice recovered from OC43 infection, even with immunostimulatory agents, reacted only with OC43 proteins and peptides and not with those from other coronaviruses. Therefore, OC43 infection in wild-type mice does not induce the heterotypic immunity observed in humans. In conclusion, OC43 induces a self-limiting lung infection in mice accompanied by homotypic lung-resident and systemic memory, amplified by proinflammatory stimuli during infection.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0