Recent advances in cell engineering technologies enable immune cells to be utilized for adoptive cell transfer (ACT) immunotherapy against cancers. Macrophages have the potential to directly and indirectly exterminate cancers and are therefore an attractive option for therapies. To develop new ACT therapies using macrophages, a great number of macrophages are required. Human induced pluripotent stem cells (iPSCs) are expected to be a source of macrophages; therefore, a system to efficiently produce macrophages from human iPSCs is needed. Here, we demonstrated that human iPSCs were robustly differentiated into macrophages by enforced FMS-like tyrosine kinase-3 (FLT3) signaling via the introduction of exogenous FLT3 into iPSCs and the addition of its ligand FLT3L to the macrophage induction culture. These iPSC-derived macrophages were identical to those obtained by standard differentiation induction methods. Thus, our novel system enables the preparation of scalable macrophages from human iPSCs. We believe that this system will be useful to develop a novel ACT therapy using macrophages.
{"title":"FLT3 signaling augments macrophage production from human pluripotent stem cells.","authors":"Kenji Kitajima, Minako Shingai, Hikaru Ando, Takahiko Hara","doi":"10.1093/intimm/dxad047","DOIUrl":"10.1093/intimm/dxad047","url":null,"abstract":"<p><p>Recent advances in cell engineering technologies enable immune cells to be utilized for adoptive cell transfer (ACT) immunotherapy against cancers. Macrophages have the potential to directly and indirectly exterminate cancers and are therefore an attractive option for therapies. To develop new ACT therapies using macrophages, a great number of macrophages are required. Human induced pluripotent stem cells (iPSCs) are expected to be a source of macrophages; therefore, a system to efficiently produce macrophages from human iPSCs is needed. Here, we demonstrated that human iPSCs were robustly differentiated into macrophages by enforced FMS-like tyrosine kinase-3 (FLT3) signaling via the introduction of exogenous FLT3 into iPSCs and the addition of its ligand FLT3L to the macrophage induction culture. These iPSC-derived macrophages were identical to those obtained by standard differentiation induction methods. Thus, our novel system enables the preparation of scalable macrophages from human iPSCs. We believe that this system will be useful to develop a novel ACT therapy using macrophages.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138794304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The activation of the anti-cancer immune system is an important strategy to control cancer. A new form of cancer phototherapy, near-infrared photoimmunotherapy (NIR-PIT), was approved for clinical use in 2020 and uses IRDye® 700DX (IR700)-conjugated antibodies and NIR light. After irradiation with NIR light, the antibody-IR700 conjugate forms water-insoluble aggregations on the plasma membrane of target cells. This aggregation causes lethal damage to the plasma membrane, and effectively leads to immunogenic cell death (ICD). Subsequently, ICD activates anti-cancer immune cells such as dendritic cells and cytotoxic T cells. Combination therapy with immune-checkpoint blockade has synergistically improved the anti-cancer effects of NIR-PIT. Additionally, NIR-PIT can eliminate immunosuppressive immune cells in light-irradiated tumors by using specific antibodies against regulatory T cells and myeloid-derived suppressor cells. In addition to cancer-cell-targeted NIR-PIT, such immune-cell-targeted NIR-PIT has shown promising results by activating the anti-cancer immune system. Furthermore, NIR-PIT can be used to manipulate the tumor microenvironment by eliminating only targeted cells in the tumor, and thus it also can be used to gain insight into immunity in basic research.
{"title":"Near-infrared photoimmunotherapy and anti-cancer immunity.","authors":"Kohei Nakajima, Mikako Ogawa","doi":"10.1093/intimm/dxad042","DOIUrl":"10.1093/intimm/dxad042","url":null,"abstract":"<p><p>The activation of the anti-cancer immune system is an important strategy to control cancer. A new form of cancer phototherapy, near-infrared photoimmunotherapy (NIR-PIT), was approved for clinical use in 2020 and uses IRDye® 700DX (IR700)-conjugated antibodies and NIR light. After irradiation with NIR light, the antibody-IR700 conjugate forms water-insoluble aggregations on the plasma membrane of target cells. This aggregation causes lethal damage to the plasma membrane, and effectively leads to immunogenic cell death (ICD). Subsequently, ICD activates anti-cancer immune cells such as dendritic cells and cytotoxic T cells. Combination therapy with immune-checkpoint blockade has synergistically improved the anti-cancer effects of NIR-PIT. Additionally, NIR-PIT can eliminate immunosuppressive immune cells in light-irradiated tumors by using specific antibodies against regulatory T cells and myeloid-derived suppressor cells. In addition to cancer-cell-targeted NIR-PIT, such immune-cell-targeted NIR-PIT has shown promising results by activating the anti-cancer immune system. Furthermore, NIR-PIT can be used to manipulate the tumor microenvironment by eliminating only targeted cells in the tumor, and thus it also can be used to gain insight into immunity in basic research.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41235050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In currently ongoing adoptive T-cell therapies, T cells collected from patients are given back to them after ex vivo activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period in order to endow T cells with the desired antigen specificity. Although such strategies are effective in some types of cancer, there remain issues to be solved: (i) the limited number of cells, (ii) it is time-consuming, (iii) it is costly, and (iv) the quality can be unstable. Points (ii) and (iv) can be solved by preparing allogeneic T cells and cryopreserving them in advance and methods are being developed using healthy donor-derived T cells or pluripotent stem cells as materials. Whereas it is difficult to solve (i) and (iii) in the former case, all the issues can be cleared in the latter case. However, in either case, a new problem arises: rejection by the patient's immune system. Deletion of human leukocyte antigen (HLA) avoids rejection by recipient T cells, but causes rejection by NK cells, which can recognize loss of HLA class I. Various countermeasures have been developed, but no definitive solution is yet available. Therefore, further research and development are necessary.
在目前正在进行的收养 T 细胞疗法中,从患者身上采集的 T 细胞经过体外激活和扩增后再还给患者。在某些情况下,T 细胞会在体外培养期间转导嵌合抗原受体(CAR)或 T 细胞受体(TCR)基因,以赋予 T 细胞所需的抗原特异性。虽然这种策略已被证明对某些类型的癌症有效,但仍有一些问题有待解决:(i) 细胞数量有限;(ii) 耗时;(iii) 成本高;(iv) 质量不稳定。第(ii)和(iv)点可以通过事先制备异体 T 细胞并将其冷冻保存来解决,使用健康供体来源的 T 细胞或多能干细胞作为材料的方法正在开发中。前者很难解决(i)和(iii),而后者则可以解决所有问题。然而,无论哪种情况,都会出现一个新问题:患者免疫系统的排斥反应。删除 HLA 可避免受体 T 细胞的排斥反应,但会引起 NK 细胞的排斥反应,因为 NK 细胞能识别 HLA I 类的缺失。
{"title":"Trends in cell medicine: from autologous cells to allogeneic universal-use cells for adoptive T-cell therapies.","authors":"Hiroshi Kawamoto, Kyoko Masuda","doi":"10.1093/intimm/dxad051","DOIUrl":"10.1093/intimm/dxad051","url":null,"abstract":"<p><p>In currently ongoing adoptive T-cell therapies, T cells collected from patients are given back to them after ex vivo activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period in order to endow T cells with the desired antigen specificity. Although such strategies are effective in some types of cancer, there remain issues to be solved: (i) the limited number of cells, (ii) it is time-consuming, (iii) it is costly, and (iv) the quality can be unstable. Points (ii) and (iv) can be solved by preparing allogeneic T cells and cryopreserving them in advance and methods are being developed using healthy donor-derived T cells or pluripotent stem cells as materials. Whereas it is difficult to solve (i) and (iii) in the former case, all the issues can be cleared in the latter case. However, in either case, a new problem arises: rejection by the patient's immune system. Deletion of human leukocyte antigen (HLA) avoids rejection by recipient T cells, but causes rejection by NK cells, which can recognize loss of HLA class I. Various countermeasures have been developed, but no definitive solution is yet available. Therefore, further research and development are necessary.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10872703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adoptive immunotherapy using chimeric antigen-receptor (CAR)-engineered T cells can induce robust antitumor responses against hematologic malignancies. However, its efficacy is not durable in the majority of the patients, warranting further improvement of T-cell functions. Cytokine signaling is one of the key cascades regulating T-cell survival and effector functions. In addition to cytokines that use the common γ chain as a receptor subunit, multiple cytokines regulate T-cell functions directly or indirectly. Modulating cytokine signaling in CAR-T cells by genetic engineering is one promising strategy to augment their therapeutic efficacy. These strategies include ectopic expression of cytokines, cytokine receptors, and synthetic molecules that mimic endogenous cytokine signaling. Alternatively, autocrine IL-2 signaling can be augmented through reprogramming of CAR-T cell properties through transcriptional and epigenetic modification. On the other hand, cytokine production by CAR-T cells triggers systemic inflammatory responses, which mainly manifest as adverse events such as cytokine-release syndrome (CRS) and neurotoxicity. In addition to inhibiting direct inflammatory mediators such as IL-6 and IL-1 released from activated macrophages, suppression of T-cell-derived cytokines associated with the priming of macrophages can be accomplished through genetic modification of CAR-T cells. In this review, I will outline recently developed synthetic biology approaches to exploit cytokine signaling to enhance CAR-T cell functions. I will also discuss therapeutic target molecules to prevent or alleviate CAR-T cell-related toxicities.
利用嵌合抗原受体(CAR)工程T细胞进行的采纳性免疫疗法可诱导针对血液系统恶性肿瘤的强大抗肿瘤反应。然而,大多数患者的疗效并不持久,因此需要进一步改善T细胞的功能。细胞因子信号转导是调节 T 细胞存活和效应功能的关键级联之一。除了使用共同的 γ 链作为受体亚基的细胞因子外,还有多种细胞因子直接或间接地调节 T 细胞功能。通过基因工程调节 CAR-T 细胞中的细胞因子信号转导是增强其疗效的一种很有前景的策略。这些策略包括异位表达细胞因子、细胞因子受体和模拟内源性细胞因子信号的合成分子。另外,还可以通过转录和表观遗传修饰对 CAR-T 细胞特性进行重编程,从而增强自分泌 IL-2 信号。另一方面,CAR-T 细胞产生的细胞因子会引发全身炎症反应,主要表现为细胞因子释放综合征(CRS)和神经毒性等不良反应。除了抑制活化巨噬细胞释放的 IL-6 和 IL-1 等直接炎症介质外,还可以通过对 CAR-T 细胞进行基因修饰来抑制与巨噬细胞引物相关的 T 细胞衍生细胞因子。在这篇综述中,我将概述最近开发的利用细胞因子信号增强 CAR-T 细胞功能的合成生物学方法。我还将讨论预防或减轻 CAR-T 细胞相关毒性的治疗靶分子。
{"title":"Cytokine signaling in chimeric antigen receptor T-cell therapy.","authors":"Yuki Kagoya","doi":"10.1093/intimm/dxad033","DOIUrl":"10.1093/intimm/dxad033","url":null,"abstract":"<p><p>Adoptive immunotherapy using chimeric antigen-receptor (CAR)-engineered T cells can induce robust antitumor responses against hematologic malignancies. However, its efficacy is not durable in the majority of the patients, warranting further improvement of T-cell functions. Cytokine signaling is one of the key cascades regulating T-cell survival and effector functions. In addition to cytokines that use the common γ chain as a receptor subunit, multiple cytokines regulate T-cell functions directly or indirectly. Modulating cytokine signaling in CAR-T cells by genetic engineering is one promising strategy to augment their therapeutic efficacy. These strategies include ectopic expression of cytokines, cytokine receptors, and synthetic molecules that mimic endogenous cytokine signaling. Alternatively, autocrine IL-2 signaling can be augmented through reprogramming of CAR-T cell properties through transcriptional and epigenetic modification. On the other hand, cytokine production by CAR-T cells triggers systemic inflammatory responses, which mainly manifest as adverse events such as cytokine-release syndrome (CRS) and neurotoxicity. In addition to inhibiting direct inflammatory mediators such as IL-6 and IL-1 released from activated macrophages, suppression of T-cell-derived cytokines associated with the priming of macrophages can be accomplished through genetic modification of CAR-T cells. In this review, I will outline recently developed synthetic biology approaches to exploit cytokine signaling to enhance CAR-T cell functions. I will also discuss therapeutic target molecules to prevent or alleviate CAR-T cell-related toxicities.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10872714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10023593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer cells employ glycolysis for their survival and growth (the "Warburg effect"). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop "immune metabolism-based precision medicine".
{"title":"Metabolic advantages of regulatory T cells dictated by cancer cells.","authors":"Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa","doi":"10.1093/intimm/dxad035","DOIUrl":"10.1093/intimm/dxad035","url":null,"abstract":"<p><p>Cancer cells employ glycolysis for their survival and growth (the \"Warburg effect\"). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop \"immune metabolism-based precision medicine\".</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41199892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic obstructive pulmonary disease (COPD) is closely related to innate and adaptive inflammatory immune responses. It is increasingly becoming evident that metabolic syndrome (MetS) affects a significant portion of COPD patients. Through this investigation, we identify shared immune-related candidate biological markers. The Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to reveal the co-expression modules linked to COPD and MetS. The commonly expressed genes in the COPD and MetS were utilized to conduct an enrichment analysis. We adopted machine-learning to screen and validate hub genes. We also assessed the relationship between hub genes and immune cell infiltration in COPD and MetS, respectively. Moreover, associations across hub genes and metabolic pathways were also explored. Finally, we chose a single-cell RNA sequencing (scRNA-seq) dataset to investigate the hub genes and shared mechanisms at the level of the cells. We also applied cell trajectory analysis and cell-cell communication analysis to focus on the vital immune cell we were interested in. As a result, we selected and validated 13 shared hub genes for COPD and MetS. The enrichment analysis and immune infiltration analysis illustrated strong associations between hub genes and immunology. Additionally, we applied metabolic pathway enrichment analysis, indicating the significant role of reactive oxygen species (ROS) in COPD with MetS. Through scRNA-seq analysis, we found that ROS might accumulate the most in the alveolar macrophages. In conclusion, the 13 hub genes related to the immune response and metabolism may serve as diagnostic biomarkers and treatment targets of COPD with MetS.
{"title":"Identification of immune-related gene signatures for chronic obstructive pulmonary disease with metabolic syndrome: evidence from integrated bulk and single-cell RNA sequencing data.","authors":"Yueren Wu, Mengyu Ma, Wenglam Choi, Weifang Xu, Jingcheng Dong","doi":"10.1093/intimm/dxad043","DOIUrl":"10.1093/intimm/dxad043","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is closely related to innate and adaptive inflammatory immune responses. It is increasingly becoming evident that metabolic syndrome (MetS) affects a significant portion of COPD patients. Through this investigation, we identify shared immune-related candidate biological markers. The Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to reveal the co-expression modules linked to COPD and MetS. The commonly expressed genes in the COPD and MetS were utilized to conduct an enrichment analysis. We adopted machine-learning to screen and validate hub genes. We also assessed the relationship between hub genes and immune cell infiltration in COPD and MetS, respectively. Moreover, associations across hub genes and metabolic pathways were also explored. Finally, we chose a single-cell RNA sequencing (scRNA-seq) dataset to investigate the hub genes and shared mechanisms at the level of the cells. We also applied cell trajectory analysis and cell-cell communication analysis to focus on the vital immune cell we were interested in. As a result, we selected and validated 13 shared hub genes for COPD and MetS. The enrichment analysis and immune infiltration analysis illustrated strong associations between hub genes and immunology. Additionally, we applied metabolic pathway enrichment analysis, indicating the significant role of reactive oxygen species (ROS) in COPD with MetS. Through scRNA-seq analysis, we found that ROS might accumulate the most in the alveolar macrophages. In conclusion, the 13 hub genes related to the immune response and metabolism may serve as diagnostic biomarkers and treatment targets of COPD with MetS.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50161482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiao Sun, Koji Hosomi, Atsushi Shimoyama, Ken Yoshii, Azusa Saika, Haruki Yamaura, Takahiro Nagatake, Hiroshi Kiyono, Koichi Fukase, Jun Kunisawa
We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103- CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.
{"title":"Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue.","authors":"Xiao Sun, Koji Hosomi, Atsushi Shimoyama, Ken Yoshii, Azusa Saika, Haruki Yamaura, Takahiro Nagatake, Hiroshi Kiyono, Koichi Fukase, Jun Kunisawa","doi":"10.1093/intimm/dxad045","DOIUrl":"10.1093/intimm/dxad045","url":null,"abstract":"<p><p>We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103- CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138440676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peripheral helper T (Tph) cells have been established, through intensive efforts to elucidate local immune responses in human rheumatoid arthritis (RA), as a CD4 subset intimately involved in acquired immunity in peripheral tissues. Initially, Tph cells were noted as a CD4 population that produces high levels of CXCL13 in RA synovial tissues, followed by a demonstration of their ability to help B cells. In contrast to follicular helper T (Tfh) cells, Tph cells do not express the transcription factor BCL6 but express molecules such as CXCL13, interleukin (IL)-21, and inducible T-cell costimulator (ICOS) to help B cells in peripheral tissues. Subsequent studies showed that Tph cells are associated with various diseases, including autoimmune diseases, infections, and malignancies, and with the development of early life immunity. This review summarizes the phenotype and function of Tph cells in RA and discusses their differentiation and diversity in various conditions.
{"title":"Peripheral helper T cells, mavericks of peripheral immune responses.","authors":"Hiroyuki Yoshitomi","doi":"10.1093/intimm/dxad041","DOIUrl":"10.1093/intimm/dxad041","url":null,"abstract":"<p><p>Peripheral helper T (Tph) cells have been established, through intensive efforts to elucidate local immune responses in human rheumatoid arthritis (RA), as a CD4 subset intimately involved in acquired immunity in peripheral tissues. Initially, Tph cells were noted as a CD4 population that produces high levels of CXCL13 in RA synovial tissues, followed by a demonstration of their ability to help B cells. In contrast to follicular helper T (Tfh) cells, Tph cells do not express the transcription factor BCL6 but express molecules such as CXCL13, interleukin (IL)-21, and inducible T-cell costimulator (ICOS) to help B cells in peripheral tissues. Subsequent studies showed that Tph cells are associated with various diseases, including autoimmune diseases, infections, and malignancies, and with the development of early life immunity. This review summarizes the phenotype and function of Tph cells in RA and discusses their differentiation and diversity in various conditions.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41118372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Highlights from International Immunology in 2023","authors":"","doi":"10.1093/intimm/dxad044","DOIUrl":"https://doi.org/10.1093/intimm/dxad044","url":null,"abstract":"","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139440141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges on several host-related factors like genetics, age, and metabolic status. Vulnerable populations, such as malnourished individuals, the obese, and the elderly, commonly exhibit diminished vaccine responses and efficacy. While the specific factors contributing to this impairment may vary, these individuals typically display a degree of metabolic dysregulation, thereby underscoring its potential significance as a fundamental determinant of suboptimal vaccine responses. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed diverse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarize the major metabolic pathways utilized by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.
疫苗接种是抗击传染病的基石,其效果取决于与宿主相关的几个因素,如遗传、年龄和新陈代谢状况。营养不良者、肥胖者和老年人等易感人群对疫苗的反应和效力通常会减弱。虽然导致这种损害的具体因素可能各不相同,但这些人通常会表现出一定程度的代谢失调,从而突出了代谢失调作为次优疫苗反应基本决定因素的潜在意义。新兴的免疫代谢领域旨在揭示免疫调节与代谢途径之间错综复杂的相互作用,最近的研究揭示了与各种疫苗反应和结果相关的各种代谢特征。在这篇综述中,我们总结了 B 细胞和 T 细胞在疫苗反应过程中利用的主要代谢途径、它们复杂多样的代谢需求以及微量营养素和代谢激素对疫苗结果的影响。此外,我们还研究了全身代谢如何影响疫苗应答,以及有证据表明易感人群的代谢失调会导致疫苗应答受损。最后,我们反思了证明代谢失调对疫苗不良反应的因果关系所面临的挑战,并强调了系统生物学方法的必要性,该方法结合了多模态分析和数学建模,以揭示这种复杂相互作用的内在机制。
{"title":"Systemic immunometabolism and responses to vaccines: insights from T and B cell perspectives.","authors":"Sam Nettelfield, Di Yu, Pablo F Cañete","doi":"10.1093/intimm/dxad021","DOIUrl":"10.1093/intimm/dxad021","url":null,"abstract":"<p><p>Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges on several host-related factors like genetics, age, and metabolic status. Vulnerable populations, such as malnourished individuals, the obese, and the elderly, commonly exhibit diminished vaccine responses and efficacy. While the specific factors contributing to this impairment may vary, these individuals typically display a degree of metabolic dysregulation, thereby underscoring its potential significance as a fundamental determinant of suboptimal vaccine responses. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed diverse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarize the major metabolic pathways utilized by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9648278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}