Lin YC, Wu CH, Chen PJ
… +5 more, Huang CH, Yang CK, Dutta A, Huang CT, Lin CY
Int Immunol
· 2023 Aug · PMID 37202206
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The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model fea...The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.
da Silva Antunes R, Grifoni A, Frazier A
… +2 more, Weiskopf D, Sette A
Int Immunol
· 2023 Aug · PMID 37148294
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In this brief opinion piece, we highlight our studies characterizing adaptive SARS-CoV-2 immune responses in infection and vaccination, and the ability of SARS-CoV-2-specific T cells to recognize emerging variants of con...In this brief opinion piece, we highlight our studies characterizing adaptive SARS-CoV-2 immune responses in infection and vaccination, and the ability of SARS-CoV-2-specific T cells to recognize emerging variants of concern, and the role of pre-existing cross-reactive T cells. In the context of the debate on correlates of protection, the pandemic's progression in the past 3 years underlined the need to consider how different adaptive immune responses might differentially contribute to protection from SARS-CoV-2 infection versus COVID-19 disease. Lastly, we discuss how cross-reactive T cell responses may be useful in generating a broad adaptive immunity, recognizing different variants and viral families. Considering vaccines with broadly conserved antigens could improve preparedness for future infectious disease outbreaks.
Nihei Y, Higashiyama M, Miyauchi K
… +4 more, Haniuda K, Suzuki Y, Kubo M, Kitamura D
Int Immunol
· 2023 Aug · PMID 37140172
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Immunoglobulin A (IgA) is the most abundant isotype of antibodies and provides a first line of defense at the mucosa against pathogens invading the host. It has been widely accepted that the mucosal IgA response provided...Immunoglobulin A (IgA) is the most abundant isotype of antibodies and provides a first line of defense at the mucosa against pathogens invading the host. It has been widely accepted that the mucosal IgA response provided by vaccination requires mucosal inoculation, and intranasal inoculation has been proposed for vaccines against influenza virus. Considering the difficulty of intranasal vaccination in infants or elderly people, however, parenteral vaccination that provides the mucosal IgA response is desirable. Here, we demonstrate that subcutaneous immunisation with zymosan, a yeast cell wall constituent known to be recognised by Dectin-1 and TLR2, potentiates the production of antigen-specific IgA antibodies in the sera and airway mucosa upon intranasal antigen challenge. We confirmed that the antigen-specific IgA-secreting cells accumulated in the lung and nasal-associated lymphoid tissues after the antigen challenge. Such an adjuvant effect of zymosan in the primary immunisation for the IgA response depended on Dectin-1 signalling, but not on TLR2. The IgA response to the antigen challenge required both antigen-specific memory B and T cells, and the generation of memory T cells, but not memory B cells, depended on zymosan as an adjuvant. Finally, we demonstrated that subcutaneous inoculation of inactivated influenza virus with zymosan, but not with alum, mostly protected the mice from infection with a lethal dose of a heterologous virus strain. These data suggest that zymosan is a possible adjuvant for parenteral immunisation that generates memory IgA responses to respiratory viruses such as influenza virus.
Int Immunol
· 2023 Aug · PMID 37086201
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Activation-induced cytidine deaminase (AID)-dependent DNA cleavage is the initial event of antibody gene-diversification processes such as class switch recombination (CSR) and somatic hypermutation (SHM). We previously r...Activation-induced cytidine deaminase (AID)-dependent DNA cleavage is the initial event of antibody gene-diversification processes such as class switch recombination (CSR) and somatic hypermutation (SHM). We previously reported the requirement of an AID-dependent decrease of topoisomerase 1 (Top1) for efficient DNA cleavage, but the underlying molecular mechanism has remained elusive. This study focuses on HuR/ELAVL1, a protein that binds to AU-rich elements in RNA. HuR-knockout (KO) CH12 cells derived from murine B lymphoma cells were found to have lower CSR and hypermutation efficiencies due to decreased AID-dependent DNA cleavage levels. The HuR-KO CH12 cells do not show impairment in cell cycles and Myc expression, which have been reported in HuR-reduced spleen B cells. Furthermore, drugs that scavenge reactive oxygen species (ROS) do not rescue the lower CSR in HuR-KO CH12 cells, meaning that ROS or decreased c-Myc protein amount is not the reason for the deficiencies of CSR and hypermutation in HuR-KO CH12 cells. We show that HuR binds to Top1 mRNA and that complete deletion of HuR abolishes AID-dependent repression of Top1 protein synthesis in CH12 cells. Additionally, reduction of CSR to IgG3 in HuR-KO cells is rescued by knockdown of Top1, indicating that elimination of the AID-dependent Top1 decrease is the cause of the inefficiency of DNA cleavage, CSR and hypermutation in HuR-KO cells. These results show that HuR is required for initiation of antibody diversification and acquired immunity through the regulation of AID-dependent DNA cleavage by repressing Top1 protein synthesis.
Natural killer (NK) cells play pivotal roles in innate immunity as well as in anti-tumor responses via natural killing, while their activity is tightly regulated by cell-surface inhibitory receptors. Immunoglobulin-like...Natural killer (NK) cells play pivotal roles in innate immunity as well as in anti-tumor responses via natural killing, while their activity is tightly regulated by cell-surface inhibitory receptors. Immunoglobulin-like transcript 3/leukocyte immunoglobulin-like receptor B4 (ILT3/LILRB4, also known as gp49B in mice) is an inhibitory receptor expressed on activated NK cells as well as myeloid-lineage cells. The common physiologic ligand of human LILRB4 and gp49B was identified very recently as fibronectin, particularly the N-terminal 30 kDa domain (FN30). We hypothesized that LILRB4 could bind fibronectin on target cells in trans together with integrins, classical fibronectin receptors, in cis and deliver an inhibitory signal in NK cells, leading to attenuated natural killing. Flow cytometric and confocal microscopic analyses of NK cell-surface gp49B and integrins suggested that these novel and classical fibronectin receptors, respectively, co-engage fibronectin immobilized on a culture plate. Biochemical analyses indicated that tyrosine phosphorylation of spleen tyrosine kinase was augmented in gp49B-deficient NK cells upon binding to the immobilized fibronectin. While surface fibronectin-poor YAC-1 cells were evenly sensitive as to natural killing of both gp49B-positive and -negative NK cells, the killing of fibronectin-rich Lewis lung carcinoma cells, but not the FN30-knockout cells, was augmented among gp49B-deficient NK cells. These results suggest that the natural cytotoxicity of NK cells is negatively regulated through LILRB4/gp49B sensing fibronectin on target cells, which sheds light on the unexpected role of LILRB4 and fibronectin as a potential attenuator of NK cell cytotoxicity in the tumor microenvironment.
For cellular or tissue transplantation using induced pluripotent stem cells (iPSCs), from the viewpoint of time and economic cost, the use of allogeneic ones is being considered. Immune regulation is one of the key issue...For cellular or tissue transplantation using induced pluripotent stem cells (iPSCs), from the viewpoint of time and economic cost, the use of allogeneic ones is being considered. Immune regulation is one of the key issues in successful allogeneic transplantation. To reduce the risk of rejection, several attempts have been reported to eliminate effects of the major histocompatibility complex (MHC) on the iPSC-derived grafts. On the other hand, we have shown that minor antigen-induced rejection is not negligible even when the MHC's impact is mitigated. In organ transplantation, it is known that donor-specific transfusion (DST) can specifically control immune responses to the donor. However, whether DST could control the immune response in iPSC-based transplantation was not clarified. In this study, using a mouse skin transplantation model, we demonstrate that infusion of donor splenocytes can promote allograft tolerance in the MHC-matched but minor antigen-mismatched conditions. When narrowing down the cell types, we found that infusion of isolated splenic B cells was sufficient to control rejection. As a mechanism, the administration of donor B cells induced unresponsiveness but not deletion in recipient T cells, suggesting that the tolerance was induced in the periphery. The donor B cell transfusion induced allogeneic iPSC engraftment. These results suggest for the first time a possibility that DST using donor B cells could induce tolerance against allogeneic iPSC-derived grafts.
Yamasaki T, Nagata N, Atsumi T
… +16 more, Hasebe R, Tanaka Y, Ohki I, Kubota S, Shinohara Y, Bin Teoh Y, Yokoyama N, Sasaki N, Nakamura K, Ohta H, Katsurada T, Matsuno Y, Hojyo S, Hashimoto S, Takiguchi M, Murakami M
Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the develo...Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD) and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2 and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G > T and c.478A>T, and found that ICRPs with the T/T SNP risk alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk alleles but no differences in serum. Moreover, we show that MMP9, which is an NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were co-localized with epithelial cells expressing MMP9 in normal colons with the risk alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also co-localized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in the intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets.
Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studie...Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.
Yang X, Yabe-Wada T, Han J
… +4 more, Saito F, Ogasawara C, Yamada S, Onai N
Int Immunol
· 2023 May · PMID 36702545
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Intestinal macrophages with functional plasticity play essential roles in gut immune responses by increasing chemokines and cytokines, thereby contributing to the pathogenesis of inflammatory bowel disease (IBD). Poly(rC...Intestinal macrophages with functional plasticity play essential roles in gut immune responses by increasing chemokines and cytokines, thereby contributing to the pathogenesis of inflammatory bowel disease (IBD). Poly(rC)-binding protein 1 (PCBP1), which is widely expressed in immune cells, binds to nucleic acids in mRNA processing, stabilization, translation and transcription. However, little is known about the influence of PCBP1 on macrophages and its specific mechanism in inflamed intestines. In this study, conditional depletion of Pcbp1 in macrophages protected mice from progression of dextran sulfate sodium induced colitis and resulted in significant alleviation of colitis. Pcbp1 deficiency markedly decreased C-C motif chemokine ligand 2 (CCL2) production by colonic CX3C motif chemokine receptor 1+ (CX3CR1+) macrophages and reduced accumulation of pro-inflammatory macrophages and production of pro-inflammatory cytokines, such as IL-6 and TNF-α, in the inflamed colon. RNA-immunoprecipitation analysis indicated that PCBP1 might interact with Ccl2 mRNA and regulate its expression in macrophages. PCBP1 expression in inflamed intestines also correlated significantly with IBD severity in patients, suggesting a critical involvement of PCBP1 in intestinal inflammation. We anticipate that our findings will facilitate the development of novel therapeutic approaches for IBD by targeting the specific function of immune cells in the local microenvironment, thereby helping to reduce adverse effects.
Int Immunol
· 2023 May · PMID 36694400
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The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the distal organs. Myeloid cells are essential for host def...The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the distal organs. Myeloid cells are essential for host defense as first responders of the host immune system. Their generation, called myelopoiesis, is regulated by environmental signals, including commensal microbiota. Hematopoietic stem and progenitor cells in bone marrow can directly or indirectly sense microbiota-derived signals, thereby giving rise to myeloid cell lineages at steady-state and during inflammation. In this review, we discuss the role of commensal microorganisms in the homeostatic regulation of myelopoiesis in the bone marrow. We also outline the effects of microbial signals on myelopoiesis during inflammation and infection, with a particular focus on the development of innate immune memory. Studying the relationship between the microbiota and myelopoiesis will help us understand how the microbiota regulates immune responses at a systemic level beyond the local mucosa.
Int Immunol
· 2023 May · PMID 36689362
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T cell independent type II (TI-II) antigens, such as capsular polysaccharides, have multivalent epitopes, which induce B cell activation, plasma cell differentiation and antibody production by strongly cross-linking B ce...T cell independent type II (TI-II) antigens, such as capsular polysaccharides, have multivalent epitopes, which induce B cell activation, plasma cell differentiation and antibody production by strongly cross-linking B cell receptors. However, the mechanism of B cell activation by TI-II antigens remains unclear. In this study, we demonstrate that DNA endonuclease DNase1L3 (also termed DNase γ) is required for the TI-II response. The production of antigen-specific antibodies was severely diminished in DNase1L3-deficient mice upon immunization with TI-II antigens, but not with T cell dependent (TD) antigens. Bone marrow chimeric mice and B cell transfer experiments revealed that B cell-intrinsic DNase1L3 was required for the TI-II response. DNase1L3-deficient B cells were defective in cell proliferation and plasma cell differentiation in the TI-II response in vivo as well as in vitro, which was not rescued by co-culture with DNase1L3-sufficient B cells in vitro, disproving an involvement of a secretory DNase1L3. In vitro stimulation with TI-II antigen transiently increased expression of DNase1L3 and its translocation into the nucleus. RNA-seq analysis of ex vivo B cells that had responded to TI-II antigen in vivo revealed a marked reduction of Myc-target gene sets in DNase1L3-deficient B cells. Expression of IRF4, a gene that Myc targets, was diminished in the ex vivo DNase1L3-deficient B cells, in which forced expression of IRF4 restored the TI-II response in vivo. These data revealed an unexpected role of DNase1L3 in a missing link between B cell receptor signaling and B cell activation in the TI-II response, giving a valuable clue to molecularly dissect this response.
Zhou Y, Li J, Wu W
… +8 more, Chen Y, Cheng H, Li M, Sun Y, Yang J, Peng D, Xue Q, Ma H
Int Immunol
· 2023 May · PMID 36591893
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Immunogenicity can be evaluated by detecting antibodies (Abs) induced by an antigen. Presently deployed assays, however, do not consider the negative impacts of Ab poly-specificity, which is well established at the monoc...Immunogenicity can be evaluated by detecting antibodies (Abs) induced by an antigen. Presently deployed assays, however, do not consider the negative impacts of Ab poly-specificity, which is well established at the monoclonal antibody level. Here, we studied antibody poly-specificity at the serum level (i.e. nonspecific Ab-probe interactions, NSIs), and ended up establishing a new platform for viral peptide immunogenicity evaluation. We first selected three peptides of high, medium and low immunogenicity, using a 'vaccine serum response rate'-based approach (i.e. the gold standard). These three peptides (Pi) in the bovine serum albumin-Pi form were used to immunize chickens, resulting in longitudinal serum samples for screening with a non-cognate peptide library. The signal intensity of Ab-peptide specific binding and 'NSI count' was used to evaluate the viral peptides' immunogenicity. Only the NSI count agreed with the gold standard. The NSI count also provides more informative data on antibody production than the aggregated signal intensity by whole-protein-based indirect enzyme-linked immunosorbent assay.
Int Immunol
· 2023 May · PMID 36573315
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BACH2 [BTB (broad-complex, tramtrak and bric à brac) and CNC (cap 'n' collar) homolog 2] is known as a transcriptional repressor and broadly functions in regulating immune cell differentiation. Here, we focus on BACH2 fu...BACH2 [BTB (broad-complex, tramtrak and bric à brac) and CNC (cap 'n' collar) homolog 2] is known as a transcriptional repressor and broadly functions in regulating immune cell differentiation. Here, we focus on BACH2 function in B cells, where BACH2 was first shown to play an important role in the immune system. In B cells, BACH2 orchestrates the gene regulatory network that promotes class switch and affinity maturation of antibodies and simultaneously represses plasma-cell differentiation. In this context, BACH2 regulates gene expression by modulating chromatin organization, cooperatively with other transcription factors and chromatin regulators, such as IRF4 (interferon regulatory factor 4) and PC4 (positive coactivator 4), respectively. In addition, our recent observation raises the possibility that BACH2 has diverse functions, such as those in gene activation. Since dysfunction of BACH2 leads to the onset of human immune deficiencies, revealing new functions of BACH2 may give a cue to solve how BACH2 contributes to preventing these diseases.
Int Immunol
· 2023 May · PMID 36566501
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Vaccination for the prevention of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is considered the most promising approach to control the pandemic of coronavirus disease 2019 (COVID-19). Alth...Vaccination for the prevention of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is considered the most promising approach to control the pandemic of coronavirus disease 2019 (COVID-19). Although various COVID-19 vaccines have been developed worldwide using several modalities, the vaccines that have shown the highest efficacy to date are mRNA vaccines. Despite their extensive usage, the mechanisms that stimulate the immune responses associated with their immunogenicity and reactogenicity remain largely unknown. In this review, we summarize and discuss current knowledge on immune responses to COVID-19 mRNA vaccines, including potential immune responses and correlating factors underlying the immunogenicity and reactogenicity of mRNA vaccines. We also describe recent trends in the optimization of lipid nanoparticles and vaccination routes. Further understanding of vaccine-elicited immune responses will guide the development of more effective and safe vaccines.
Yu Y, Li M, Fu S
… +9 more, He X, Hu X, Zhu G, Wang J, You X, Mou Y, Ye Z, Wei J, Zha Y
Int Immunol
· 2023 May · PMID 36534968
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Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a p...Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a putative therapeutic target in many of these diseases. However, no pharmacological inhibitor of RIPK1-mediated cell death is currently in clinical use. Recognizing that a repurposed drug has an expedited clinical development pipeline, here we performed a high-throughput drug screen of Food and Drug Administration (FDA)-approved compounds and identified a novel use for crizotinib as an inhibitor of RIPK1-dependent cell death. Furthermore, crizotinib rescued TNF-α-induced death in mice with systemic inflammatory response syndrome. RIPK1 kinase activity was directly inhibited by crizotinib. These findings identify a new use for an established compound and are expected to accelerate drug development for RIPK1-spectrum disorders.
Int Immunol
· 2023 Apr · PMID 36525591
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Osteopontin (OPN) is a multifunctional protein, initially identified in osteosarcoma cells with its role of mediating osteoblast adhesion. Later studies revealed that OPN is associated with many inflammatory conditions c...Osteopontin (OPN) is a multifunctional protein, initially identified in osteosarcoma cells with its role of mediating osteoblast adhesion. Later studies revealed that OPN is associated with many inflammatory conditions caused by infections, allergic responses, autoimmunity and tissue damage. Many cell types in the peripheral immune system express OPN with various functions, which could be beneficial or detrimental. Also, more recent studies demonstrated that OPN is highly expressed in the central nervous system (CNS), particularly in microglia during CNS diseases and development. However, understanding of mechanisms underlying OPN's functions in the CNS is still limited. In this review, we focus on peripheral myeloid cells and CNS-resident cells to discuss the expression and functions of OPN.
The RNA-binding proteins Roquin-1/2 and Regnase-1 exert essential regulation by controlling pro-inflammatory mRNA expression to prevent autoimmune disease. More recently, inhibition of this post-transcriptional gene regu...The RNA-binding proteins Roquin-1/2 and Regnase-1 exert essential regulation by controlling pro-inflammatory mRNA expression to prevent autoimmune disease. More recently, inhibition of this post-transcriptional gene regulatory program has been demonstrated to enable enhanced anti-tumor responses by tumor antigen-specific CD8+ T cells. In this review, we describe the functions of these RNA-binding proteins and the phenotypes that arise in association with genetic inhibition or inactivation. We discuss how inducible inactivation of the system reprograms CD4+ and CD8+ T cell fates by changing cell metabolism, activation, differentiation or effector/memory decisions. We furthermore outline what we need to know to precisely modulate this system in order to dampen autoimmune reactions or boost the efficacy of adoptively transferred T cells or chimeric antigen receptor (CAR) T cells in cancer immunotherapies.
Tokumaru S, Yamamoto Y, Yoshizawa K
… +3 more, Soejima Y, Sanjo H, Taki S
Int Immunol
· 2023 May · PMID 36521002
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CD8αα+ intestinal intraepithelial lymphocytes (iIELs) are known for their unique role in keeping the integrity of the intestinal epithelial barrier, but factors affecting the development of these cells have not been thor...CD8αα+ intestinal intraepithelial lymphocytes (iIELs) are known for their unique role in keeping the integrity of the intestinal epithelial barrier, but factors affecting the development of these cells have not been thoroughly understood. Here, we found that the transcriptional regulator interferon regulatory factor-2 (IRF-2) plays a cell-intrinsic, indispensable role in establishing iIEL populations. CD8αα+, but not CD8αβ+, iIELs bearing TCRαβ or TCRγδ were severely reduced in numbers in mice lacking this factor (Irf2-/- mice). Moreover, the majority of residual CD8αα+TCRαβ+ iIELs in these mice was immature as judged from their Thy1.2high phenotype and inefficient T-bet expression. Thymic IEL precursors isolated from Irf2-/- mice failed to efficiently generate CD8αα+TCRαβ+ and TCRγδ+ IELs upon transfer in vivo and CD8αα+TCRαβ+ cells in response to IL-15 in vitro. Double mutant mice lacking both interleukin-15 (IL-15) and IRF-2 showed an even more severe iIEL defect than in mice lacking IL-15 alone. Upon increasing agonistic TCR signal strength through OT-II TCR transgenesis, CD8αα+TCRαβ+ iIELs became more abundant but remained immature on the Irf2-/- background. Our current observations, thus, revealed the unique bimodal role that IRF-2 plays in promoting not only generation of IEL progenitors in the thymus but also maturation of iIELs in the periphery in IL-15-dependent and -independent manners.
Asahi T, Abe S, Tajika Y
… +4 more, Rodewald HR, Sexl V, Takeshima H, Ikuta K
Int Immunol
· 2023 Mar · PMID 36480702
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Group 1 innate lymphoid cells (G1-ILCs) are innate immune effectors critical for the response to intracellular pathogens and tumors. G1-ILCs comprise circulating natural killer (NK) cells and tissue-resident type 1 ILCs...Group 1 innate lymphoid cells (G1-ILCs) are innate immune effectors critical for the response to intracellular pathogens and tumors. G1-ILCs comprise circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s). ILC1s mainly reside in barrier tissues and provide the initial sources of interferon-γ (IFN-γ) to prime the protecting responses against infections, which are followed by the response of recruited NK cells. Despite such distribution differences, whether local environmental factors influence the behavior of NK cells and ILC1s is unclear. Here, we show that the signaling of retinoic acid (RA), active metabolites of vitamin A, is essential for the maintenance of ILC1s in the periphery. Mice expressing RARα403, a truncated form of retinoic acid receptor α (RARα) that exerts dominant negative activity, in a lymphoid cell- or G1-ILC-specific manner showed remarkable reductions of peripheral ILC1s while NK cells were unaffected. Lymphoid cell-specific inhibition of RAR activity resulted in the reduction of PD-1+ ILC progenitors (ILCPs), but not of common lymphoid progenitors (CLPs), suggesting the impaired commitment and differentiation of ILC1s. Transcriptome analysis revealed that RARα403-expressing ILC1s exhibited impaired proliferative states and declined expression of effector molecules. Thus, our findings demonstrate that cell-intrinsic RA signaling is required for the homeostasis and the functionality of ILC1s, which may present RA as critical environmental cue targeting local type 1 immunity against infection and cancer.