Journal of immunology最新文献_第2页

Depletion of eosinophils during sensitization but not challenge phase in mice blocks the development of food allergy early in life.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-06 DOI: 10.1093/jimmun/vkae044

Haoran Gao, Allison E Kosins, Joel A Ochoa, Elizabeth A Jacobsen, Joan M Cook-Mills

{"title":"Depletion of eosinophils during sensitization but not challenge phase in mice blocks the development of food allergy early in life.","authors":"Haoran Gao, Allison E Kosins, Joel A Ochoa, Elizabeth A Jacobsen, Joan M Cook-Mills","doi":"10.1093/jimmun/vkae044","DOIUrl":"https://doi.org/10.1093/jimmun/vkae044","url":null,"abstract":"Food allergy can be life threatening and often develops early in life, especially in infants and children with atopic dermatitis. Food allergy is induced in neonatal mice with skin barrier mutations (Flaky Tail, FT+/- mice with filaggrin and mattrin gene mutations) by epicutaneous sensitization with co-exposures to the food allergen peanut extract (PNE), the environmental allergen Alternaria alternata (Alt), and detergent (4% SDS); oral PNE-challenge induces anaphylaxis. Sensitization in these neonates also induces eosinophil infiltration into the skin and elevates skin expression of eotaxins (CCL11 and CCL24). However, roles for eosinophils in food allergy are not known. In this study, the iPhil+/- FT+/- pups, which have an inducible eosinophil-deficiency upon injection of diphtheria toxin (DTX), were sensitized and then received PNE by gavage to assess anaphylaxis. DTX depletion of eosinophils, during sensitization and oral PNE-challenge, blocked the recruitment and activation of mast cells, blocked the Alt+PNE-induced increase in plasma IL-33 and OSM, attenuated serum PNE-specific IgE/IgG1/IgG2b, and blocked oral-PNE-induced anaphylaxis. Anti-IL-5 depletion of eosinophils during sensitization/challenge also blocked anaphylaxis. When eosinophils were depleted during allergen-skin-sensitization and restored before oral PNE-challenge, anaphylaxis was blocked. In contrast, when eosinophils were present during allergen-skin-sensitization but then depleted during oral PNE-challenge, anaphylaxis was not blocked. Together, these data indicate that although eosinophils are not necessary during oral food allergen-induced anaphylaxis, eosinophils have a critical role during the development of food allergy early in life by regulating the sensitization-induced increase in mast cell numbers and food allergen-specific IgE.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615572","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

Aging and neurodegeneration: when systemic dysregulations affect brain macrophage heterogeneity.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-06 DOI: 10.1093/jimmun/vkae034

Paul Joly, Reyhane Labsy, Aymeric Silvin

引用次数: 0

Quantitative detection of the HVEM-BTLA checkpoint receptor cis-complex in human lymphocytes.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-05 DOI: 10.1093/jimmun/vkae057

Shane Atwell, Timothy C Cheung, Elaine M Conner, Carolyn Ho, Jiawen Huang, Erin L Harryman, Ricky Lieu, Stacie Lim, Wai W Lin, Diana I Ruiz, Andrew C Vendel, Carl F Ware

{"title":"Quantitative detection of the HVEM-BTLA checkpoint receptor cis-complex in human lymphocytes.","authors":"Shane Atwell, Timothy C Cheung, Elaine M Conner, Carolyn Ho, Jiawen Huang, Erin L Harryman, Ricky Lieu, Stacie Lim, Wai W Lin, Diana I Ruiz, Andrew C Vendel, Carl F Ware","doi":"10.1093/jimmun/vkae057","DOIUrl":"https://doi.org/10.1093/jimmun/vkae057","url":null,"abstract":"The herpesvirus entry mediator (HVEM) (TNFRSF14) engagement of the checkpoint inhibitory receptor B and T lymphocyte attenuator (BTLA) limits immune responses of T and B lymphocytes. HVEM and BTLA form signaling complexes in trans and when coexpressed, complexes in cis, creating a unique immune checkpoint. The function of the HVEM-BTLA cis-complex is not well understood primarily due to a lack of reagents that specifically measure the HVEM-BTLA cis-complex. We describe here a method to generate antibodies to receptor-ligand complexes using fusion immunogens, in this case, a BTLA-HVEM fusion protein. We identified 2 closely related antibodies that specifically recognize the HVEM-BTLA complex on the cell surface. In experiments utilizing the anti-HVEM-BTLA complex-specific antibody together with subunit-specific BTLA monoclonal antibodies, we were able to determine the precise ratio of free to cis-complexed BTLA on subpopulations of human lymphocytes. This is the first direct quantification of the HVEM-BTLA cis-complex. The method described here should apply to the detection of other receptor-ligand complexes.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615656","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

Comparison of human macrophages derived from peripheral blood and bone marrow.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-05 DOI: 10.1093/jimmun/vkae032

Hannah L Smith, Russell B Foxall, Patrick J Duriez, Emma L Teal, Adam D Hoppe, Janos M Kanczler, Juliet C Gray, Stephen A Beers

{"title":"Comparison of human macrophages derived from peripheral blood and bone marrow.","authors":"Hannah L Smith, Russell B Foxall, Patrick J Duriez, Emma L Teal, Adam D Hoppe, Janos M Kanczler, Juliet C Gray, Stephen A Beers","doi":"10.1093/jimmun/vkae032","DOIUrl":"https://doi.org/10.1093/jimmun/vkae032","url":null,"abstract":"Macrophage differentiation, phenotype, and function have been assessed extensively in vitro by predominantly deriving human macrophages from peripheral blood. It is accepted that there are differences between macrophages isolated from different human tissues; however, the importance of anatomical source for in vitro differentiation and characterization is less clear. Here, phenotype and function were evaluated between human macrophages derived from bone marrow or peripheral blood. Macrophages were differentiated by adherence of heterogenous cell populations or CD14 isolation and polarized with IFNγ and LPS or IL-4 and IL-13 for 48 hours before evaluation of phenotype and phagocytic capacity. The presence of stromal cells in bone marrow heterogenous cultures resulted in a reduction in macrophage purity compared to peripheral blood, which was negated after CD14 isolation. Phenotypically, monocyte-derived macrophages (MDMs) derived from peripheral blood and bone marrow resulted in similar expression of classical and polarized macrophages markers, including CD14, HLA-DR, CD38, and CD40 (increased after IFNγ/LPS), and CD11b and CD206 (elevated after IL-4/IL-13). Functionally, these cells also showed similar levels of Fc-independent and Fc-dependent phagocytosis, although there was a nonsignificant reduction of Fc-dependent phagocytosis in the bone marrow derived macrophages after IFNγ/LPS stimulation. In summary, we have identified that human MDMs differentiated from peripheral blood and bone marrow showed similar characteristics and functionality, suggesting that isolating cells from different anatomical niches does not affect macrophage differentiation after CD14 isolation. Consequently, due to high yield and ready availability peripheral blood derived macrophages are still the most suitable source.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615558","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

Zebrafish (Danio rerio) TDP43 negatively regulates PKZ-IRF3-mediated IFN I response.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-05 DOI: 10.1093/jimmun/vkae035

Tingting Yu, Miaomiao Li, Meifeng Li, Shanghong Wang, Zhiqing Feng, Hongying Zhang, Jiwei Liu, Huiling Mao, Dongming Li, Chengyu Hu, Xiaowen Xu

{"title":"Zebrafish (Danio rerio) TDP43 negatively regulates PKZ-IRF3-mediated IFN I response.","authors":"Tingting Yu, Miaomiao Li, Meifeng Li, Shanghong Wang, Zhiqing Feng, Hongying Zhang, Jiwei Liu, Huiling Mao, Dongming Li, Chengyu Hu, Xiaowen Xu","doi":"10.1093/jimmun/vkae035","DOIUrl":"https://doi.org/10.1093/jimmun/vkae035","url":null,"abstract":"Transactive response DNA binding protein 43 kD (TDP43), encoded by the tardbp gene, is a member of heterogenous nuclear ribonucleoproteins family. In this study, a gradual upregulation of TDP43 messenger RNA was observed in either Ctenopharyngodon idella kidney cells or zebrafish following stimulation with B-DNA, grass carp reovirus, or spring viremia of carp virus. Moreover, grass carp reovirus stimulation enhances the dimerization, phosphorylation, and cytoplasm-to-nucleus translocation of TDP43 in zebrafish (DrTDP43). Type I interferon (IFN I) expression is inhibited in a dose-dependent manner in the cells transfected with DrTDP43 under GCRV stimulation. These results indicated that DrTDP43 is involved in innate immune response and serves as a negative regulator of IFN I expression. To determine DrTDP43-dependent downstream pathway in innate immunity, the substrate of DrTDP43 was studied. It is known that IFN I expression can be activated by PKZ via IRF3 dependent pathway. Our results found that DrTDP43 can be interacted with PKZ, suggesting that the downregulation of IFN I by DrTDP43 may attribute to the inhibition of PKZ activity. Multiple DrTDP43 mutants were constructed to further reveal the mechanism of TDP43-PKZ-mediated IFN I response. Apart from the N-terminal domain, RNA recognition motif 1, RNA recognition motif 2, and low-complexity domain domains of DrTDP43 were all found to be involved in inhibiting phosphorylation of PKZ. In vivo, knockdown of TDP43 in zebrafish embryos improved embryo survival rate upon viral infection and upregulated expression of IFN I. In summary, our findings demonstrate that DrTDP43 is a negative regulator of IFN I expression through the inhibition of the PKZ-IRF3-dependent pathway.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615744","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

Gut IgA-antibody secreting cells segregate into four Blimp1+ subsets based on differential expression of IgA and Ki-67 and are retained following prolonged αCD20 B cell depletion in mice.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-05 DOI: 10.1093/jimmun/vkae046

Savannah D Neu, Cody J Gurski, Nathan J Meinhardt, Kevin C Jennings, Bonnie N Dittel

{"title":"Gut IgA-antibody secreting cells segregate into four Blimp1+ subsets based on differential expression of IgA and Ki-67 and are retained following prolonged αCD20 B cell depletion in mice.","authors":"Savannah D Neu, Cody J Gurski, Nathan J Meinhardt, Kevin C Jennings, Bonnie N Dittel","doi":"10.1093/jimmun/vkae046","DOIUrl":"https://doi.org/10.1093/jimmun/vkae046","url":null,"abstract":"B cell depletion is an efficacious therapy for multiple sclerosis, but its long-term safety profile in the gastrointestinal tract has not been specifically studied. This is of importance because the gut is the largest reservoir of IgA in the body, which maintains gut homeostasis in part by regulating the composition of the gut microbiota. This was addressed by development of a prolonged B cell depletion model using human CD20 transgenic mice and B cell depletion with the anti-human CD20 antibodies rituximab, a humanized mouse monoclonal, and 2H7, the mouse precursor to ocrelizumab. Both antibodies depleted B cells in the spleen, mesenteric lymph nodes, small intestine, and large intestine, with 2H7 being more efficient. Because gut IgA+ antibody secreting cells (ASC) are poorly defined a flow cytometry strategy was developed using differential expression of IgA and Ki-67 by Blimp1+ cells that identified four IgA-ASC subsets across a developmental spectrum. Neither antibody was efficacious in depleting of any IgA-ASC subset in the intestines. Consequently, fecal IgA levels and percentage of IgA-bound fecal microbes were unaltered. Cumulatively, these studies demonstrate that prolonged B cell-depletion did not substantially impact IgA levels nor overall gut health, providing important insight into the safety profile of B cell depletion drugs.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615676","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

Myeloid-derived IL-33 drives γδ T cell-dependent resistance against cutaneous infection by Strongyloides ratti.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-04 DOI: 10.1093/jimmun/vkae038

Erin Evonne Jean, Heather Lynn Rossi, Li Yin Hung, Juan M Inclan-Rico, De'Broski R Herbert

{"title":"Myeloid-derived IL-33 drives γδ T cell-dependent resistance against cutaneous infection by Strongyloides ratti.","authors":"Erin Evonne Jean, Heather Lynn Rossi, Li Yin Hung, Juan M Inclan-Rico, De'Broski R Herbert","doi":"10.1093/jimmun/vkae038","DOIUrl":"https://doi.org/10.1093/jimmun/vkae038","url":null,"abstract":"Interleukin 33 (IL-33) is a pleiotropic cytokine released from diverse cell types that regulate both pro- and anti-inflammatory responses during pathogen infection. However, it remains unclear whether IL-33 controls key aspects of cutaneous immunity against skin-penetrating parasites. In this study, mice percutaneously infected with the parasitic helminth Strongyloides ratti were investigated to understand mechanisms of anamnestic immunity at the skin barrier. Surprisingly, mice lacking the Type 2 transcription factor STAT6 (signal transducer and activator of transcription 6) had no defects in secondary resistance to infection, whereas IL-33 gene deficiency or local blockade of IL-33 receptor (ST2) signaling abrogated host resistance. Depletion of CD4+ T cells or type 2 innate lymphoid cells had only a moderate impact on protection, but the loss of γδ T cells completely ablated cutaneous immunity against rechallenge. We identified a CD62Lhi IL-33 receptor (ST2)-expressing γδ T cell population that accumulated in the skin of protected mice that was dependent upon IL-33 expression in myeloid lineage antigen-presenting cells. This work suggests a previously unrecognized mechanism wherein noncanonical type 2 immunity operates through myeloid antigen-presenting cells and skin γδ T cells to adaptively repel skin-penetrating helminth larvae.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615698","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

Absence of c-Maf and IL-10 enables type I IFN enhancement of innate responses to LPS in alveolar macrophages.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-03 DOI: 10.1093/jimmun/vkae029

Pamelia N Lim, Maritza M Cervantes, Linh K Pham, Sydney R Doherty, Ankita Tufts, Divya Dubey, Dat Mai, Alan Aderem, Alan H Diercks, Alissa C Rothchild

{"title":"Absence of c-Maf and IL-10 enables type I IFN enhancement of innate responses to LPS in alveolar macrophages.","authors":"Pamelia N Lim, Maritza M Cervantes, Linh K Pham, Sydney R Doherty, Ankita Tufts, Divya Dubey, Dat Mai, Alan Aderem, Alan H Diercks, Alissa C Rothchild","doi":"10.1093/jimmun/vkae029","DOIUrl":"https://doi.org/10.1093/jimmun/vkae029","url":null,"abstract":"Alveolar macrophages (AMs) are lung-resident myeloid cells and airway sentinels for inhaled pathogens and environmental particles. While AMs can be highly inflammatory in response to respiratory viruses, they do not mount proinflammatory responses to all airborne pathogens. For example, we previously showed that AMs fail to mount a robust proinflammatory response to Mycobacterium tuberculosis. Here, we address this discrepancy by investigating the capacity of murine AMs for direct innate immune sensing, using LPS as a model. Use of LPS-coated fluorescent beads enabled us to distinguish between directly exposed and bystander cells to measure transcriptional responses, by RNA-sequencing after cell sorting, and cytokine responses, by flow cytometry. We find that AMs have decreased proinflammatory responses to low-dose LPS compared to other macrophage types (bone marrow-derived macrophages, peritoneal macrophages), as measured by TNF, IL-6, Ifnb, and Ifit3. The reduced response to low-dose LPS correlates with minimal TLR4 and CD14 surface expression, despite sufficient internal expression of TLR4. We also find that AMs do not produce IL-10 in response to a variety of stimuli due to low expression of the transcription factor c-Maf, while exogenous c-Maf expression restores IL-10 production in AMs. Lastly, we show that lack of IL-10 enables type I IFN enhancement of AM responses to LPS. Overall, we demonstrate AMs have a cell-intrinsic hyporesponsiveness to LPS, which makes them uniquely tolerant to low-dose exposure. Regulation of AM innate responses by distinct CD14, c-Maf, and IL-10 expression patterns has important implications for both respiratory infections and environmental airborne exposures.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615414","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

Inhibitory immunoreceptors CD300a and CD300lf cooperate to regulate mast cell activation.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-03 DOI: 10.1093/jimmun/vkae030

Hanbin Lee, Chigusa Nakahashi-Oda, Wenxin Lyu, Mamoru Tanaka, Akiyoshi Rai, Yoichi Muramoto, Yaqiu Wang, Seiya Mizuno, Kazuko Shibuya, Akira Shibuya

{"title":"Inhibitory immunoreceptors CD300a and CD300lf cooperate to regulate mast cell activation.","authors":"Hanbin Lee, Chigusa Nakahashi-Oda, Wenxin Lyu, Mamoru Tanaka, Akiyoshi Rai, Yoichi Muramoto, Yaqiu Wang, Seiya Mizuno, Kazuko Shibuya, Akira Shibuya","doi":"10.1093/jimmun/vkae030","DOIUrl":"https://doi.org/10.1093/jimmun/vkae030","url":null,"abstract":"Mast cells (MCs) play a central role in allergic immune responses. MC activation is regulated by several inhibitory immunoreceptors. The CD300 family members CD300a and CD300lf recognize phospholipid ligands and inhibit the FcεRI-mediated activating signal in MCs. While CD300a binds to phosphatidylserine (PS) to inhibit MCs activation, CD300lf function is less clear due to its ability to bind with ceramide and PS. Moreover, it also remains blurring whether CD300a and CD300lf function independently, cooperatively, or by interfering with each other in regulating MC activation. Using imaging and flow cytometric analyses of bone marrow-derived cultured MCs (BMMCs) from wild-type (WT), Cd300a-/-, Cd300lf-/-, and Cd300a-/-Cd300lf-/- mice, we show that CD300lf and CD300a colocalized with PS externalized to the outer leaflet of the plasma membrane with a polar formation upon activation, and CD300lf cooperates with CD300a to inhibit BMMCs activation. CD300lf also colocalized with extracellular ceramide in addition to the internal PS on the cell surface, which results in stronger inhibition of MC activation than CD300lf binding to PS alone. Similarly, although both Cd300a-/- and Cd300lf-/- mice showed decreased rectal temperatures compared with WT mice in the model of passive systemic anaphylaxis, Cd300a-/-Cd300lf-/- mice showed lower rectal temperature than either Cd300a-/- or Cd300lf-/- mice. Our results demonstrate the cooperativity of multiple inhibitory receptors expressed on MCs and their regulatory functions upon binding to respective ligands.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615686","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 aryl hydrocarbon receptor controls IFN-γ-induced immune checkpoints PD-L1 and IDO via the JAK/STAT pathway in lung adenocarcinoma.

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-03 DOI: 10.1093/jimmun/vkae023

Megan Snyder, Zhongyan Wang, Brian Lara, Jocelyn Fimbres, Táchira Pichardo, Sarah Mazzilli, Mohammed Muzamil Khan, Vinay K Duggineni, Stefano Monti, David H Sherr

{"title":"The aryl hydrocarbon receptor controls IFN-γ-induced immune checkpoints PD-L1 and IDO via the JAK/STAT pathway in lung adenocarcinoma.","authors":"Megan Snyder, Zhongyan Wang, Brian Lara, Jocelyn Fimbres, Táchira Pichardo, Sarah Mazzilli, Mohammed Muzamil Khan, Vinay K Duggineni, Stefano Monti, David H Sherr","doi":"10.1093/jimmun/vkae023","DOIUrl":"https://doi.org/10.1093/jimmun/vkae023","url":null,"abstract":"While immunotherapy has shown some efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation, the AhR, a known but counterintuitive mediator of immunosuppression (interferon (IFN)-γ), and regulation of two immune checkpoints (PD-L1 and IDO). AhR gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk and scRNA sequencing of LUADs and tumor-infiltrating T cells were used to map out a signaling pathway leading from IFN-γ through the AhR to JAK/STAT, PD-L1, IDO, and tumor-mediated immunosuppression. The data demonstrate that: (1) IFN-γ activation of the JAK/STAT pathway leading to PD-L1 and IDO1 up-regulation is mediated by the AhR in murine and human LUAD cells, (2) AhR-driven IDO1 induction results in the production of Kynurenine (Kyn), an AhR ligand, which likely mediates an AhR→IDO1→Kyn→AhR amplification loop, (3) transplantation of AhR-knockout LUAD cells results in long-term tumor immunity in most recipients. (4) The 23% of AhR-knockout tumors that do grow do so at a much slower pace than controls and exhibit higher densities of CD8+ T cells expressing markers of immunocompetence, increased activity, and increased cell-cell communication. The data definitively link the AhR to IFN-γ-induced JAK/STAT pathway and immune checkpoint-mediated immunosuppression and support the targeting of the AhR in the context of LUAD.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615735","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