Pub Date : 2024-03-01DOI: 10.4049/immunohorizons.2300083
Haoran Yang, Naoki Iwanaga, Alexis R Katz, Andy R Ridley, Haiyan D Miller, Michaela J Allen, Dereck Pociask, Jay K Kolls
T cell immunity, including CD4+ and CD8+ T cell immunity, is critical to host immune responses to infection. Transcriptomic analyses of both CD4+ and CD8+ T cells of C57BL/6 mice show high expression the gene encoding embigin, Emb, which encodes a transmembrane glycoprotein. Moreover, we found that lung CD4+ Th17 tissue-resident memory T cells of C57BL/6 mice also express high levels of Emb. However, deletion of Emb in αβ T cells of C57BL/6 mice revealed that Emb is dispensable for thymic T cell development, generation of lung Th17 tissue-resident memory T cells, tissue-resident memory T cell homing to the lung, experimental autoimmune encephalitis, as well as clearance of pulmonary viral or fungal infection. Thus, based on this study, embigin appears to play a minor role if any in αβ T cell development or αβ T cell effector functions in C57BL/6 mice.
T 细胞免疫,包括 CD4+ 和 CD8+ T 细胞免疫,对于宿主对感染的免疫反应至关重要。对 C57BL/6 小鼠 CD4+ 和 CD8+ T 细胞的转录组分析表明,编码 Emb 的基因表达量很高,Emb 是一种跨膜糖蛋白。此外,我们还发现 C57BL/6 小鼠肺部 CD4+ Th17 组织驻留记忆 T 细胞也高水平表达 Emb。然而,在 C57BL/6 小鼠的 αβ T 细胞中缺失 Emb 后发现,Emb 对胸腺 T 细胞的发育、肺 Th17 组织驻留记忆 T 细胞的生成、组织驻留记忆 T 细胞归巢到肺、实验性自身免疫性脑炎以及清除肺部病毒或真菌感染都是不可或缺的。因此,根据这项研究,embigin似乎在C57BL/6小鼠的αβ T细胞发育或αβ T细胞效应功能中只起了很小的作用。
{"title":"Embigin Is Highly Expressed on CD4+ and CD8+ T Cells but Is Dispensable for Several T Cell Effector Responses.","authors":"Haoran Yang, Naoki Iwanaga, Alexis R Katz, Andy R Ridley, Haiyan D Miller, Michaela J Allen, Dereck Pociask, Jay K Kolls","doi":"10.4049/immunohorizons.2300083","DOIUrl":"10.4049/immunohorizons.2300083","url":null,"abstract":"<p><p>T cell immunity, including CD4+ and CD8+ T cell immunity, is critical to host immune responses to infection. Transcriptomic analyses of both CD4+ and CD8+ T cells of C57BL/6 mice show high expression the gene encoding embigin, Emb, which encodes a transmembrane glycoprotein. Moreover, we found that lung CD4+ Th17 tissue-resident memory T cells of C57BL/6 mice also express high levels of Emb. However, deletion of Emb in αβ T cells of C57BL/6 mice revealed that Emb is dispensable for thymic T cell development, generation of lung Th17 tissue-resident memory T cells, tissue-resident memory T cell homing to the lung, experimental autoimmune encephalitis, as well as clearance of pulmonary viral or fungal infection. Thus, based on this study, embigin appears to play a minor role if any in αβ T cell development or αβ T cell effector functions in C57BL/6 mice.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140041201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant.
{"title":"Fatty Acids Play a Critical Role in Mitochondrial Oxidative Phosphorylation in Effector T Cells in Graft-versus-Host Disease.","authors":"Hirofumi Nakano, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Takashi Ikeda, Shin-Ichiro Kawaguchi, Kiyomi Mashima, Kento Umino, Kaoru Morita, Ryoji Ito, Nobuhiko Ohno, Kaoru Tominaga, Hitoshi Endo, Yoshinobu Kanda","doi":"10.4049/immunohorizons.2300115","DOIUrl":"10.4049/immunohorizons.2300115","url":null,"abstract":"<p><p>Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140029851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01DOI: 10.4049/immunohorizons.2300109
Joshua S Mytych, Zijian Pan, Charmaine Lopez-Davis, Nancy Redinger, Christina Lawrence, Jadith Ziegler, Narcis I Popescu, Judith A James, A Darise Farris
Bacillus anthracis peptidoglycan (PGN) is a major component of the bacterial cell wall and a key pathogen-associated molecular pattern contributing to anthrax pathology, including organ dysfunction and coagulopathy. Increases in apoptotic leukocytes are a late-stage feature of anthrax and sepsis, suggesting there is a defect in apoptotic clearance. In this study, we tested the hypothesis that B. anthracis PGN inhibits the capacity of human monocyte-derived macrophages (MΦ) to efferocytose apoptotic cells. Exposure of CD163+CD206+ MΦ to PGN for 24 h impaired efferocytosis in a manner dependent on human serum opsonins but independent of complement component C3. PGN treatment reduced cell surface expression of the proefferocytic signaling receptors MERTK, TYRO3, AXL, integrin αVβ5, CD36, and TIM-3, whereas TIM-1, αVβ3, CD300b, CD300f, STABILIN-1, and STABILIN-2 were unaffected. ADAM17 is a major membrane-bound protease implicated in mediating efferocytotic receptor cleavage. We found multiple ADAM17-mediated substrates increased in PGN-treated supernatant, suggesting involvement of membrane-bound proteases. ADAM17 inhibitors TAPI-0 and Marimastat prevented TNF release, indicating effective protease inhibition, and modestly increased cell-surface levels of MerTK and TIM-3 but only partially restored efferocytic capacity by PGN-treated MΦ. We conclude that human serum factors are required for optimal recognition of PGN by human MΦ and that B. anthracis PGN inhibits efferocytosis in part by reducing cell surface expression of MERTK and TIM-3.
{"title":"Peptidoglycan from Bacillus anthracis Inhibits Human Macrophage Efferocytosis in Part by Reducing Cell Surface Expression of MERTK and TIM-3.","authors":"Joshua S Mytych, Zijian Pan, Charmaine Lopez-Davis, Nancy Redinger, Christina Lawrence, Jadith Ziegler, Narcis I Popescu, Judith A James, A Darise Farris","doi":"10.4049/immunohorizons.2300109","DOIUrl":"10.4049/immunohorizons.2300109","url":null,"abstract":"<p><p>Bacillus anthracis peptidoglycan (PGN) is a major component of the bacterial cell wall and a key pathogen-associated molecular pattern contributing to anthrax pathology, including organ dysfunction and coagulopathy. Increases in apoptotic leukocytes are a late-stage feature of anthrax and sepsis, suggesting there is a defect in apoptotic clearance. In this study, we tested the hypothesis that B. anthracis PGN inhibits the capacity of human monocyte-derived macrophages (MΦ) to efferocytose apoptotic cells. Exposure of CD163+CD206+ MΦ to PGN for 24 h impaired efferocytosis in a manner dependent on human serum opsonins but independent of complement component C3. PGN treatment reduced cell surface expression of the proefferocytic signaling receptors MERTK, TYRO3, AXL, integrin αVβ5, CD36, and TIM-3, whereas TIM-1, αVβ3, CD300b, CD300f, STABILIN-1, and STABILIN-2 were unaffected. ADAM17 is a major membrane-bound protease implicated in mediating efferocytotic receptor cleavage. We found multiple ADAM17-mediated substrates increased in PGN-treated supernatant, suggesting involvement of membrane-bound proteases. ADAM17 inhibitors TAPI-0 and Marimastat prevented TNF release, indicating effective protease inhibition, and modestly increased cell-surface levels of MerTK and TIM-3 but only partially restored efferocytic capacity by PGN-treated MΦ. We conclude that human serum factors are required for optimal recognition of PGN by human MΦ and that B. anthracis PGN inhibits efferocytosis in part by reducing cell surface expression of MERTK and TIM-3.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140186745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01DOI: 10.4049/immunohorizons.2400003
Nicholas Magazine, Tianyi Zhang, Anang D Bungwon, Michael C McGee, Yingying Wu, Gianluca Veggiani, Weishan Huang
Despite the success of global vaccination programs in slowing the spread of COVID-19, these efforts have been hindered by the emergence of new SARS-CoV-2 strains capable of evading prior immunity. The mutation and evolution of SARS-CoV-2 have created a demand for persistent efforts in vaccine development. SARS-CoV-2 Spike protein has been the primary target for COVID-19 vaccine development, but it is also the hotspot of mutations directly involved in host susceptibility and virus immune evasion. Our ability to predict emerging mutants and select conserved epitopes is critical for the development of a broadly neutralizing therapy or a universal vaccine. In this article, we review the general paradigm of immune responses to COVID-19 vaccines, highlighting the immunological epitopes of Spike protein that are likely associated with eliciting protective immunity resulting from vaccination in humans. Specifically, we analyze the structural and evolutionary characteristics of the SARS-CoV-2 Spike protein related to immune activation and function via the TLRs, B cells, and T cells. We aim to provide a comprehensive analysis of immune epitopes of Spike protein, thereby contributing to the development of new strategies for broad neutralization or universal vaccination.
{"title":"Immune Epitopes of SARS-CoV-2 Spike Protein and Considerations for Universal Vaccine Development.","authors":"Nicholas Magazine, Tianyi Zhang, Anang D Bungwon, Michael C McGee, Yingying Wu, Gianluca Veggiani, Weishan Huang","doi":"10.4049/immunohorizons.2400003","DOIUrl":"10.4049/immunohorizons.2400003","url":null,"abstract":"<p><p>Despite the success of global vaccination programs in slowing the spread of COVID-19, these efforts have been hindered by the emergence of new SARS-CoV-2 strains capable of evading prior immunity. The mutation and evolution of SARS-CoV-2 have created a demand for persistent efforts in vaccine development. SARS-CoV-2 Spike protein has been the primary target for COVID-19 vaccine development, but it is also the hotspot of mutations directly involved in host susceptibility and virus immune evasion. Our ability to predict emerging mutants and select conserved epitopes is critical for the development of a broadly neutralizing therapy or a universal vaccine. In this article, we review the general paradigm of immune responses to COVID-19 vaccines, highlighting the immunological epitopes of Spike protein that are likely associated with eliciting protective immunity resulting from vaccination in humans. Specifically, we analyze the structural and evolutionary characteristics of the SARS-CoV-2 Spike protein related to immune activation and function via the TLRs, B cells, and T cells. We aim to provide a comprehensive analysis of immune epitopes of Spike protein, thereby contributing to the development of new strategies for broad neutralization or universal vaccination.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01DOI: 10.4049/immunohorizons.2300108
Ryan M Baxter, Berenice Cabrera-Martinez, Tusharkanti Ghosh, Cody Rester, Miguel Guerrero Moreno, Tyler L Borko, Sean Selva, Chelsie L Fleischer, Nicola Haakonsen, Ariana Mayher, Emily Bowhay, Courtney Evans, Todd M Miller, Leah Huey, Jennifer McWilliams, Adrie van Bokhoven, Kevin D Deane, Vijaya Knight, Kimberly R Jordan, Debashis Ghosh, Jared Klarquist, Ross M Kedl, Amanda L Piquet, Elena W Y Hsieh
The impact of B cell deficiency on the humoral and cellular responses to SARS-CoV2 mRNA vaccination remains a challenging and significant clinical management question. We evaluated vaccine-elicited serological and cellular responses in 1) healthy individuals who were pre-exposed to SARS-CoV-2 (n = 21), 2) healthy individuals who received a homologous booster (mRNA, n = 19; or Novavax, n = 19), and 3) persons with multiple sclerosis on B cell depletion therapy (MS-αCD20) receiving mRNA homologous boosting (n = 36). Pre-exposure increased humoral and CD4 T cellular responses in immunocompetent individuals. Novavax homologous boosting induced a significantly more robust serological response than mRNA boosting. MS-α CD20 had an intact IgA mucosal response and an enhanced CD8 T cell response to mRNA boosting compared with immunocompetent individuals. This enhanced cellular response was characterized by the expansion of only effector, not memory, T cells. The enhancement of CD8 T cells in the setting of B cell depletion suggests a regulatory mechanism between B and CD8 T cell vaccine responses.
B 细胞缺乏对接种 SARS-CoV2 mRNA 疫苗后体液和细胞反应的影响仍然是一个具有挑战性的重要临床管理问题。我们评估了疫苗引起的血清学和细胞反应:1)预先暴露于 SARS-CoV-2 的健康人(n = 21);2)接种同源加强剂(mRNA,n = 19;或 Novavax,n = 19)的健康人;3)接受 B 细胞耗竭疗法(MS-αCD20)的多发性硬化症患者,接种 mRNA 同源加强剂(n = 36)。在免疫功能正常的个体中,预暴露可增加体液和 CD4 T 细胞反应。与 mRNA 同源增强相比,Novavax 同源增强诱导的血清反应明显更强。与免疫功能正常的人相比,MS-α CD20 对 mRNA 增强具有完整的 IgA 粘膜反应和增强的 CD8 T 细胞反应。这种增强的细胞反应的特点是只扩增效应T细胞,而不是记忆T细胞。在 B 细胞耗竭的情况下 CD8 T 细胞的增强表明 B 细胞和 CD8 T 细胞疫苗反应之间存在一种调节机制。
{"title":"SARS-CoV-2 Vaccine-Elicited Immunity after B Cell Depletion in Multiple Sclerosis.","authors":"Ryan M Baxter, Berenice Cabrera-Martinez, Tusharkanti Ghosh, Cody Rester, Miguel Guerrero Moreno, Tyler L Borko, Sean Selva, Chelsie L Fleischer, Nicola Haakonsen, Ariana Mayher, Emily Bowhay, Courtney Evans, Todd M Miller, Leah Huey, Jennifer McWilliams, Adrie van Bokhoven, Kevin D Deane, Vijaya Knight, Kimberly R Jordan, Debashis Ghosh, Jared Klarquist, Ross M Kedl, Amanda L Piquet, Elena W Y Hsieh","doi":"10.4049/immunohorizons.2300108","DOIUrl":"10.4049/immunohorizons.2300108","url":null,"abstract":"<p><p>The impact of B cell deficiency on the humoral and cellular responses to SARS-CoV2 mRNA vaccination remains a challenging and significant clinical management question. We evaluated vaccine-elicited serological and cellular responses in 1) healthy individuals who were pre-exposed to SARS-CoV-2 (n = 21), 2) healthy individuals who received a homologous booster (mRNA, n = 19; or Novavax, n = 19), and 3) persons with multiple sclerosis on B cell depletion therapy (MS-αCD20) receiving mRNA homologous boosting (n = 36). Pre-exposure increased humoral and CD4 T cellular responses in immunocompetent individuals. Novavax homologous boosting induced a significantly more robust serological response than mRNA boosting. MS-α CD20 had an intact IgA mucosal response and an enhanced CD8 T cell response to mRNA boosting compared with immunocompetent individuals. This enhanced cellular response was characterized by the expansion of only effector, not memory, T cells. The enhancement of CD8 T cells in the setting of B cell depletion suggests a regulatory mechanism between B and CD8 T cell vaccine responses.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140121681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01DOI: 10.4049/immunohorizons.2300079
Breanna Caruso, Benjamin R Weeder, Reid F Thompson, Amy E Moran
Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been studied extensively in peripheral T cell responses to foreign Ags, self-Ags, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of murine PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and programmed death-ligand 1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs because other agonist selected cell populations, such as NK T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1-deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggest that PD-1-deficient thymocytes produce elevated levels of IL-2, a Treg niche-limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of murine thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.
在外周 T 细胞对外来抗原、自身抗原和新抗原的反应中,对抑制蛋白(如程序性细胞死亡蛋白 1 (PD-1))进行了广泛的研究。值得注意的是,这些蛋白最初是在胸腺中的 T 细胞发育过程中表达的。有报告表明,PD-1 限制了调节性 T 细胞(Treg)的发育,但 PD-1 发挥这一功能的机制仍不清楚。本研究扩大了对小鼠胸腺中 PD-1 及其配体的评估,证明 PD-1 和程序性死亡配体 1 的一些最高表达者是经过激动剂选择的细胞。令人惊讶的是,我们揭示了 PD-1 在调节发育龛位方面只对 Tregs 起选择性作用,因为其他激动剂选择细胞群(如 NK T 细胞)保持不变。我们还排除了 PD-1 作为激动剂选择的 Treg 增殖或细胞死亡调节因子的可能性,并进一步证明了 PD-1 缺失的 Treg 的 TCR 信号传导能力降低。意想不到的是,数据表明 PD-1 缺陷胸腺细胞产生的 IL-2 水平升高,而 IL-2 是一种 Treg 龛限制细胞因子。总之,这些数据表明 PD-1 在调节 IL-2 的产生和小鼠胸腺 Tregs 的同步激动剂选择方面发挥了新的作用。这一观察结果对在癌症和感染背景下使用检查点阻断疗法具有重要意义。
{"title":"PD-1 Limits IL-2 Production and Thymic Regulatory T Cell Development.","authors":"Breanna Caruso, Benjamin R Weeder, Reid F Thompson, Amy E Moran","doi":"10.4049/immunohorizons.2300079","DOIUrl":"10.4049/immunohorizons.2300079","url":null,"abstract":"<p><p>Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been studied extensively in peripheral T cell responses to foreign Ags, self-Ags, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of murine PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and programmed death-ligand 1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs because other agonist selected cell populations, such as NK T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1-deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggest that PD-1-deficient thymocytes produce elevated levels of IL-2, a Treg niche-limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of murine thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140320247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.4049/immunohorizons.2400004
Yuhang Wang
Erythroid differentiation regulator 1 (Erdr1) is a stress-induced, widely expressed, highly conserved secreted factor found in both humans and mice. Erdr1 is linked with the Hippo-YAP1 signaling. Initially identified as an inducer of hemoglobin synthesis, Erdr1 emerged as a multifunctional protein, especially in immune cells. Although Erdr1 has been implicated in regulating T cells and NK cell function, its role in macrophage remains unclear. This study explored the function and mechanism of Erdr1 in macrophage inflammatory response. The data demonstrated that Erdr1 could promote anti-inflammatory cytokine production, a function that also has been reported by previous research. However, I found Erdr1 also could play a proinflammatory role. The function of Erdr1 in macrophages depends on its dose and cell density. I observed that Erdr1 expression was inhibited in M1 macrophages but was upregulated in M2 macrophages compared with unpolarized macrophages. I hypothesized that Erdr1 balances the inflammatory response by binding with distinct adaptors dependent on varying concentrations. Mechanistically, I demonstrated YAP1 and Mid1 as the two adaptor proteins of Erdr1. The Erdr1-YAP1 interaction promotes anti-inflammatory cytokine production when Erdr1 levels are elevated, whereas the Erdr1-Mid1 interaction induces proinflammatory cytokine production when Erdr1 levels are decreased. This study highlights the effects of Erdr1 on regulating cytokine production from polarized macrophages potentially by regulating YAP1 in the nonclassical Hippo pathway.
{"title":"Erdr1 Drives Macrophage Programming via Dynamic Interplay with YAP1 and Mid1.","authors":"Yuhang Wang","doi":"10.4049/immunohorizons.2400004","DOIUrl":"10.4049/immunohorizons.2400004","url":null,"abstract":"<p><p>Erythroid differentiation regulator 1 (Erdr1) is a stress-induced, widely expressed, highly conserved secreted factor found in both humans and mice. Erdr1 is linked with the Hippo-YAP1 signaling. Initially identified as an inducer of hemoglobin synthesis, Erdr1 emerged as a multifunctional protein, especially in immune cells. Although Erdr1 has been implicated in regulating T cells and NK cell function, its role in macrophage remains unclear. This study explored the function and mechanism of Erdr1 in macrophage inflammatory response. The data demonstrated that Erdr1 could promote anti-inflammatory cytokine production, a function that also has been reported by previous research. However, I found Erdr1 also could play a proinflammatory role. The function of Erdr1 in macrophages depends on its dose and cell density. I observed that Erdr1 expression was inhibited in M1 macrophages but was upregulated in M2 macrophages compared with unpolarized macrophages. I hypothesized that Erdr1 balances the inflammatory response by binding with distinct adaptors dependent on varying concentrations. Mechanistically, I demonstrated YAP1 and Mid1 as the two adaptor proteins of Erdr1. The Erdr1-YAP1 interaction promotes anti-inflammatory cytokine production when Erdr1 levels are elevated, whereas the Erdr1-Mid1 interaction induces proinflammatory cytokine production when Erdr1 levels are decreased. This study highlights the effects of Erdr1 on regulating cytokine production from polarized macrophages potentially by regulating YAP1 in the nonclassical Hippo pathway.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.4049/immunohorizons.2300093
Young Min Son, In Su Cheon, Chaofan Li, Jie Sun
Emerging studies have identified the critical roles of tissue-resident memory CD8+ T (TRM) and B (BRM) cells in the protection against mucosal viral infections, but the underlying mechanisms regulating robust development of TRM and BRM cells remain incompletely understood. We have recently shown that tissue-resident helper CD4+ T (TRH) cells, developed following influenza virus infection, function to sustain the optimal maintenance of TRM and BRM cells at the mucosal surface. In this study, we have explored the cellular and molecular cues modulating lung TRH persistence after influenza infection in C57BL/6 mice. We found that TRH cells were colocalized in tertiary lymphoid structures (TLSs) with local B cells. Abolishing TLSs or the depletion of B cells impaired lung TRH cell numbers. Of note, we found that persistent TCR signaling is needed for the maintenance of TRH cells after the clearance of infectious influenza virus. Furthermore, selective ablation of B cell-derived MHC class II resulted in partial reduction of lung TRH cell number after influenza infection. Our findings suggest that the interaction between lung-resident TRH cells and B cells, along with persistent Ag stimulation, is required to maintain TRH cells after respiratory viral infection.
新近的研究发现,组织驻留记忆 CD8+ T 细胞(TRM)和 B 细胞(BRM)在抵御粘膜病毒感染方面发挥着关键作用,但人们对调控 TRM 和 BRM 细胞稳健发育的内在机制仍然知之甚少。我们最近的研究表明,流感病毒感染后形成的组织驻留辅助 CD4+ T(TRH)细胞具有维持粘膜表面 TRM 和 BRM 细胞最佳维持状态的功能。在这项研究中,我们探索了调节C57BL/6小鼠感染流感后肺部TRH持久性的细胞和分子线索。我们发现,TRH细胞与局部B细胞共定位在三级淋巴结构(TLS)中。消除三级淋巴结构或减少 B 细胞会影响肺 TRH 细胞的数量。值得注意的是,我们发现在传染性流感病毒清除后,TRH细胞的维持需要持续的TCR信号。此外,选择性消减B细胞衍生的MHC II类导致流感感染后肺TRH细胞数量部分减少。我们的研究结果表明,肺驻留的TRH细胞与B细胞之间的相互作用以及持续的Ag刺激是在呼吸道病毒感染后维持TRH细胞所必需的。
{"title":"Persistent B Cell-Derived MHC Class II Signaling Is Required for the Optimal Maintenance of Tissue-Resident Helper T Cells.","authors":"Young Min Son, In Su Cheon, Chaofan Li, Jie Sun","doi":"10.4049/immunohorizons.2300093","DOIUrl":"10.4049/immunohorizons.2300093","url":null,"abstract":"<p><p>Emerging studies have identified the critical roles of tissue-resident memory CD8+ T (TRM) and B (BRM) cells in the protection against mucosal viral infections, but the underlying mechanisms regulating robust development of TRM and BRM cells remain incompletely understood. We have recently shown that tissue-resident helper CD4+ T (TRH) cells, developed following influenza virus infection, function to sustain the optimal maintenance of TRM and BRM cells at the mucosal surface. In this study, we have explored the cellular and molecular cues modulating lung TRH persistence after influenza infection in C57BL/6 mice. We found that TRH cells were colocalized in tertiary lymphoid structures (TLSs) with local B cells. Abolishing TLSs or the depletion of B cells impaired lung TRH cell numbers. Of note, we found that persistent TCR signaling is needed for the maintenance of TRH cells after the clearance of infectious influenza virus. Furthermore, selective ablation of B cell-derived MHC class II resulted in partial reduction of lung TRH cell number after influenza infection. Our findings suggest that the interaction between lung-resident TRH cells and B cells, along with persistent Ag stimulation, is required to maintain TRH cells after respiratory viral infection.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139725450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.4049/immunohorizons.2300107
Laurisa M Ankley, Kayla N Conner, Taryn E Vielma, Jared J Godfrey, Mahima Thapa, Andrew J Olive
Macrophages play a crucial role in eliminating respiratory pathogens. Both pulmonary resident alveolar macrophages (AMs) and recruited macrophages contribute to detecting, responding to, and resolving infections in the lungs. Despite their distinct functions, it remains unclear how these macrophage subsets regulate their responses to infection, including how activation by the cytokine IFN-γ is regulated. This shortcoming prevents the development of therapeutics that effectively target distinct lung macrophage populations without exacerbating inflammation. We aimed to better understand the transcriptional regulation of resting and IFN-γ-activated cells using a new ex vivo model of AMs from mice, fetal liver-derived alveolar-like macrophages (FLAMs), and immortalized bone marrow-derived macrophages. Our findings reveal that IFN-γ robustly activates both macrophage types; however, the profile of activated IFN-γ-stimulated genes varies greatly between these cell types. Notably, FLAMs show limited expression of costimulatory markers essential for T cell activation upon stimulation with only IFN-γ. To understand cell type-specific differences, we examined how the inhibition of the regulatory kinases GSK3α/β alters the IFN-γ response. GSK3α/β controlled distinct IFN-γ responses, and in AM-like cells, we found that GSK3α/β restrained the induction of type I IFN and TNF, thus preventing the robust expression of costimulatory molecules and limiting CD4+ T cell activation. Together, these data suggest that the capacity of AMs to respond to IFN-γ is restricted in a GSK3α/β-dependent manner and that IFN-γ responses differ across distinct macrophage populations. These findings lay the groundwork to identify new therapeutic targets that activate protective pulmonary responses without driving deleterious inflammation.
{"title":"GSK3α/β Restrain IFN-γ-Inducible Costimulatory Molecule Expression in Alveolar Macrophages, Limiting CD4+ T Cell Activation.","authors":"Laurisa M Ankley, Kayla N Conner, Taryn E Vielma, Jared J Godfrey, Mahima Thapa, Andrew J Olive","doi":"10.4049/immunohorizons.2300107","DOIUrl":"10.4049/immunohorizons.2300107","url":null,"abstract":"<p><p>Macrophages play a crucial role in eliminating respiratory pathogens. Both pulmonary resident alveolar macrophages (AMs) and recruited macrophages contribute to detecting, responding to, and resolving infections in the lungs. Despite their distinct functions, it remains unclear how these macrophage subsets regulate their responses to infection, including how activation by the cytokine IFN-γ is regulated. This shortcoming prevents the development of therapeutics that effectively target distinct lung macrophage populations without exacerbating inflammation. We aimed to better understand the transcriptional regulation of resting and IFN-γ-activated cells using a new ex vivo model of AMs from mice, fetal liver-derived alveolar-like macrophages (FLAMs), and immortalized bone marrow-derived macrophages. Our findings reveal that IFN-γ robustly activates both macrophage types; however, the profile of activated IFN-γ-stimulated genes varies greatly between these cell types. Notably, FLAMs show limited expression of costimulatory markers essential for T cell activation upon stimulation with only IFN-γ. To understand cell type-specific differences, we examined how the inhibition of the regulatory kinases GSK3α/β alters the IFN-γ response. GSK3α/β controlled distinct IFN-γ responses, and in AM-like cells, we found that GSK3α/β restrained the induction of type I IFN and TNF, thus preventing the robust expression of costimulatory molecules and limiting CD4+ T cell activation. Together, these data suggest that the capacity of AMs to respond to IFN-γ is restricted in a GSK3α/β-dependent manner and that IFN-γ responses differ across distinct macrophage populations. These findings lay the groundwork to identify new therapeutic targets that activate protective pulmonary responses without driving deleterious inflammation.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139725449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.4049/immunohorizons.2300105
M Quinn Peters, Eva Domenjo-Vila, Marc Carlson, Blair Armistead, Paul T Edlefsen, Melanie Gasper, Smritee Dabee, Christopher Whidbey, Heather B Jaspan, Martin Prlic, Whitney E Harrington
T cells in the human female genital tract (FGT) are key mediators of susceptibility to and protection from infection, including HIV and other sexually transmitted infections. There is a critical need for increased understanding of the distribution and activation of T cell populations in the FGT, but current sampling methods require a healthcare provider and are expensive, limiting the ability to study these populations longitudinally. To address these challenges, we have developed a method to sample immune cells from the FGT utilizing disposable menstrual discs which are noninvasive, self-applied, and low in cost. To demonstrate reproducibility, we sampled the cervicovaginal fluid of healthy, reproductive-aged individuals using menstrual discs across 3 sequential days. Cervicovaginal fluid was processed for cervicovaginal cells, and high-parameter flow cytometry was used to characterize immune populations. We identified large numbers of live, CD45+ leukocytes, as well as distinct populations of T cells and B cells. Within the T cell compartment, activation and suppression status of T cell subsets were consistent with previous studies of the FGT utilizing current approaches, including identification of both tissue-resident and migratory populations. In addition, the T cell population structure was highly conserved across days within individuals but divergent across individuals. Our approach to sample immune cells in the FGT with menstrual discs will decrease barriers to participation and empower longitudinal sampling in future research studies.
人类女性生殖道(FGT)中的 T 细胞是易受感染和免受感染(包括 HIV 和其他性传播感染)的关键介质。我们亟需进一步了解 FGT 中 T 细胞群的分布和活化情况,但目前的采样方法需要医疗保健提供者,而且费用昂贵,限制了对这些细胞群进行纵向研究的能力。为了应对这些挑战,我们开发了一种利用一次性月经盘从 FGT 提取免疫细胞样本的方法,这种方法无创、可自行应用且成本低廉。为了证明这种方法的可重复性,我们使用月经盘连续三天对健康育龄个体的宫颈阴道液进行采样。我们对宫颈阴道液进行了处理,以检测宫颈阴道细胞,并使用高参数流式细胞术鉴定免疫群体的特征。我们发现了大量活的 CD45+ 白细胞,以及不同的 T 细胞和 B 细胞群。在 T 细胞区系中,T 细胞亚群的活化和抑制状态与之前利用现有方法对 FGT 进行的研究一致,包括组织驻留和迁移群的鉴定。此外,T细胞群体结构在个体内部不同天数之间高度一致,但在个体之间存在差异。我们利用月经盘对 FGT 中的免疫细胞进行采样的方法将减少参与研究的障碍,并有助于在未来的研究中进行纵向采样。
{"title":"A Noninvasive Method to Sample Immune Cells in the Lower Female Genital Tract Using Menstrual Discs.","authors":"M Quinn Peters, Eva Domenjo-Vila, Marc Carlson, Blair Armistead, Paul T Edlefsen, Melanie Gasper, Smritee Dabee, Christopher Whidbey, Heather B Jaspan, Martin Prlic, Whitney E Harrington","doi":"10.4049/immunohorizons.2300105","DOIUrl":"10.4049/immunohorizons.2300105","url":null,"abstract":"<p><p>T cells in the human female genital tract (FGT) are key mediators of susceptibility to and protection from infection, including HIV and other sexually transmitted infections. There is a critical need for increased understanding of the distribution and activation of T cell populations in the FGT, but current sampling methods require a healthcare provider and are expensive, limiting the ability to study these populations longitudinally. To address these challenges, we have developed a method to sample immune cells from the FGT utilizing disposable menstrual discs which are noninvasive, self-applied, and low in cost. To demonstrate reproducibility, we sampled the cervicovaginal fluid of healthy, reproductive-aged individuals using menstrual discs across 3 sequential days. Cervicovaginal fluid was processed for cervicovaginal cells, and high-parameter flow cytometry was used to characterize immune populations. We identified large numbers of live, CD45+ leukocytes, as well as distinct populations of T cells and B cells. Within the T cell compartment, activation and suppression status of T cell subsets were consistent with previous studies of the FGT utilizing current approaches, including identification of both tissue-resident and migratory populations. In addition, the T cell population structure was highly conserved across days within individuals but divergent across individuals. Our approach to sample immune cells in the FGT with menstrual discs will decrease barriers to participation and empower longitudinal sampling in future research studies.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}