Members of the Batf family, including Batf, Batf2, and Batf3, play critical roles in various immune cell types. Several studies have suggested redundant functions, as they can compensate for each other's functions. Here,...Members of the Batf family, including Batf, Batf2, and Batf3, play critical roles in various immune cell types. Several studies have suggested redundant functions, as they can compensate for each other's functions. Here, we show that transduction of Batf family members confers distinct functional characteristics on CD8+ T cells. Batf- and Batf2-transduced CD8+ T cells exhibited effector and memory-like phenotypes, respectively. Notably, Batf3-transduced CD8+ T cells showed both effector- and memory-like phenotypes in response to effector- and memory-associated cytokines, respectively, and superior anti-tumor activity in vivo among Batf family members. Our results demonstrated that each Batf family member has distinct functions in CD8+ T cells. These findings help us understand the roles of the Batf family members in CD8+ T cells and contribute to the development of optimized adoptive T cell therapies against cancer.
Mori D, Sax N, Shimada N
… +9 more, Kuwabara M, Ebina I, Omiya R, Hattori K, Shinnakasu R, Yamashita K, Yamasaki S, Kurosaki T, Ise W
Int Immunol
· 2026 Jun · PMID 41664926
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CD4+ T helper (Th) cells play a central role in orchestrating protective immune responses during infection and vaccination. Activation of naïve CD4+ T cells is initiated by the recognition of antigenic peptides presented...CD4+ T helper (Th) cells play a central role in orchestrating protective immune responses during infection and vaccination. Activation of naïve CD4+ T cells is initiated by the recognition of antigenic peptides presented on MHC class II (MHC-II) molecules, leading to their differentiation into distinct effector subsets. In the context of influenza virus infection, the quality of CD4+ T-cell responses is a critical determinant of both cellular and humoral immunity. Given the limited breadth of protection conferred by current influenza vaccines, which primarily induce strain-specific neutralizing antibodies, there is growing interest in harnessing CD4+ T-cell responses targeting conserved viral epitopes to achieve broader and more durable protection. Identifying potent T-cell epitopes within viral antigens is therefore critical for designing effective vaccines that elicit robust, durable, and cross-protective Th-cell and antibody responses. In this study, using a mouse model of influenza virus infection, we identified CD4+ T-cell epitopes within the hemagglutinin (HA) and nucleoprotein (NP) of the H1N1 strain. We generated two NP peptide/MHC-II tetramers, NP264-274/I-Ab and NP418-428/I-Ab, which enabled in vivo tracking and characterization of epitope-specific CD4+ T cells during infection. These epitope-specific T cells exhibited distinct T-cell receptor (TCR) repertoires and differentiation patterns toward either Th1 or T follicular helper (Tfh) lineages, suggesting that epitope specificity shapes the quality of the T-cell response. Our findings provide new insights into the epitope-dependent functional diversity of Th-cell responses and offer valuable tools for the rational design of broadly protective influenza vaccines.
Int Immunol
· 2026 Jun · PMID 41630420
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In human blood B cells exist in a variety of forms ranging from antigen-inexperienced naive cells to long-term memory cells, and antibody-producing plasma cells. Historically, the divisions between these types of cells h...In human blood B cells exist in a variety of forms ranging from antigen-inexperienced naive cells to long-term memory cells, and antibody-producing plasma cells. Historically, the divisions between these types of cells have been defined by a few characteristic surface markers such as IgD, CD27, and CD21, but recent advances in single-cell techniques such as high-parameter cytometry and single-cell sequencing have revealed a greater diversity of populations. An expanding palette of markers has helped to better define B cell subsets but can be a source of confusion when overlapping cell types are identified using different sets of markers. In this review, we will discuss the conflicting and overlapping phenotypic and functional identities of human circulating B cells with a particular emphasis on memory B cells. We also propose a framework in which five B cell markers (IgD, CD27, CD21, CD11c, and a glycosylated isoform of CD45RB) can discriminate the majority of B cell populations in human blood.
Int Immunol
· 2026 Jul · PMID 41614233
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The bone tissue serves as a dynamic reservoir that accommodates diverse immune cell populations during low-energy states such as fasting. Energy restriction and reduced metabolism induce a transient migration of naïve B...The bone tissue serves as a dynamic reservoir that accommodates diverse immune cell populations during low-energy states such as fasting. Energy restriction and reduced metabolism induce a transient migration of naïve B cells from Peyer's patches to the bone marrow in mice, a process driven by the upregulation of Cxcl13 expression within the bone niche. However, the specific cellular source of CXCL13 and the upstream signals regulating its expression remain undefined. Our analysis identified the lineage-negative fraction of the bone as the major source of CXCL13. Single-cell RNA sequencing of these cells further demonstrated that Cxcl13 was selectively expressed by osteogenic mesenchymal stromal cells (MSCs) during fasting. Consistently, immunofluorescence imaging showed an increased frequency of these CXCL13-producing cells under fasting conditions, primarily localized within the perivascular niche. Gene Ontology analysis of differentially expressed genes in these cells during fasting revealed enrichment of TGF-β and PPAR signaling. In line with this, pharmacological intervention in either the TGF-β or PPARγ signaling pathway significantly attenuated fasting-induced naïve B-cell migration and CXCL13 production in the bone. These results establish a mechanistic link between systemic metabolic cues and the bone marrow immune microenvironment. We propose that osteogenic MSCs play a vital role in orchestrating this trafficking program for naïve B cells, underscoring a dynamic crosstalk between the bone stromal cells and the immune system.
Xu P, Ueha S, Aoki H
… +8 more, Kitabatake M, Chen M, Shichino S, Hara A, Ouji-Sageshima N, Ito T, Motozono C, Matsushima K
Int Immunol
· 2026 Jun · PMID 41540901
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Successive mRNA vaccinations preserve severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell immunity, but how individual CD8⁺ T-cell clones behave across repeated booster doses and breakthrough inf...Successive mRNA vaccinations preserve severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell immunity, but how individual CD8⁺ T-cell clones behave across repeated booster doses and breakthrough infection (BTI) remains poorly defined. We longitudinally tracked bulk CD8⁺ T-cell receptor beta (TCRβ) repertoires and spike-specific tetramer⁺ CD8⁺ T cells in adult participants across the third and fourth vaccine doses and subsequent BTI. Each booster continued to recruit previously unexpanded "new" responder clonotypes, but both the number and summed frequency of newly engaged clones declined with successive doses. In contrast, clones first recruited by the initial prime-boost doses-particularly those expanded after Dose 2-formed a durable, hierarchically dominant memory pool that persisted for >2 years yet displayed progressively attenuated recall with later boosters. BTI revealed a complementary mode of repertoire remodeling: newly engaged clones that had not responded to prior vaccinations showed the strongest, but transient, expansion, broadening the antigenic targets beyond spike. On the other hand, vaccine-induced clones showed limited recall response while sustaining their dominance in the long term. Together, these findings indicate that repeated mRNA vaccination maintains a stable pool of early-established CD8⁺ T-cell clones but progressively limits their recall capacity, whereas BTI mobilizes additional, partially distinct clonotypes that expand robustly and broaden antigenic coverage.
Xue Y, Tai Y, Yamamoto H
… +12 more, Mori D, Sakai K, Miyazaki T, Owa M, Kometani K, Ebina I, Omiya R, Hattori K, Inoue T, Ise W, Shinnakasu R, Kurosaki T
Int Immunol
· 2026 Jun · PMID 41540896
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The development of vaccines eliciting broadly neutralizing influenza antibodies (bnAbs) is an extraordinary challenge. One hypothetical proposal is that CD4+ T-cell help to rare immuno-subdominant bnAb class memory B cel...The development of vaccines eliciting broadly neutralizing influenza antibodies (bnAbs) is an extraordinary challenge. One hypothetical proposal is that CD4+ T-cell help to rare immuno-subdominant bnAb class memory B cells is one critical factor to cause these B cells to re-enter secondary germinal centers (GCs) and generate potent bnAbs. In this regard, we previously showed that the prototypic hemagglutinin stem vaccine does not contain the dominant CD4+ T-cell epitope. Here, to test the above hypothesis, we examined the effects of adding a single influenza T-cell epitope to the stem vaccine in an influenza pre-infected booster mouse model. We found that this fused booster vaccine efficiently recruited antistem memory B cells with prior GC experience into the secondary GCs in draining lymph nodes. Furthermore, these secondary GC-experienced cells evolved, thereby contributing to generation of more potent neutralizing activity toward variant viruses. Thus, our results suggest the importance of T-cell help in generating potent bnAbs by recruiting rare subdominant memory B cells into secondary GCs, and have implications for vaccine design.
Kimura U, Matsuyama N, Saiki K
… +4 more, Kashima S, Takahashi H, Takaya A, Tokoyoda K
Int Immunol
· 2026 May · PMID 41428362
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Intracellular bacteria can survive in vivo, evading host immunity and antibiotics. Salmonella persists in organs such as the spleen by invading the phagocytic cells. However, it remains controversial which specific cell...Intracellular bacteria can survive in vivo, evading host immunity and antibiotics. Salmonella persists in organs such as the spleen by invading the phagocytic cells. However, it remains controversial which specific cell populations, e.g. macrophages, monocytes, neutrophils, or dendritic cells, harbor the bacteria during persistent infection. To address this question, we employed a persistent infection mouse model using attenuated Salmonella expressing an acid tolerant fluorescent protein. We found that the bacteria predominantly resided in monocytes. Although these cells expressed Ly-6G, a typical marker for neutrophils, they did not exhibit a polymorphonuclear morphology. Furthermore, Salmonella primarily and preferentially invaded monocytes over other phagocytic cell types. Importantly, Salmonella was able to survive in monocytes even in the presence of antibiotics. Our findings demonstrate that monocytes serve as a critical survival niche for Salmonella in vivo, allowing the bacteria to evade both host immunity and antibiotics.
Int Immunol
· 2026 May · PMID 41414849
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In early life, the immune and nervous systems are highly plastic and engage in complex, bidirectional communication that is critical for establishing postnatal immune tolerance, gut and brain development, and responses t...In early life, the immune and nervous systems are highly plastic and engage in complex, bidirectional communication that is critical for establishing postnatal immune tolerance, gut and brain development, and responses to environmental challenges. The developing gut microbiota exerts its influence on both systems via microbial metabolites to modulate immune responses and neural function. Early disruptions in the gut microbiota, in part because of preterm delivery or antibiotic treatment, are linked to long-term immune or neurodevelopmental impairments. In this review, we provide an overview of the current understanding of how the microbiota crosstalk with immune cells regulates the development and function of the nervous system.
Kamiyama N, Saechue B, Sachi N
… +10 more, Chalalai T, Dewayani A, Okamoto M, Ozaka S, Soga Y, Kagoshima Y, Ekronarongchai S, Hidano S, Tsuda M, Kobayashi T
Int Immunol
· 2026 May · PMID 41403257
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Recent outbreaks of the ZIKA virus (ZIKV) in Brazil and Puerto Rico have been linked to an increase in the incidence of fetal microcephaly and Guillain-Barré syndrome. In addition, although a causal relationship remains...Recent outbreaks of the ZIKA virus (ZIKV) in Brazil and Puerto Rico have been linked to an increase in the incidence of fetal microcephaly and Guillain-Barré syndrome. In addition, although a causal relationship remains unproven, ZIKV has been found in the brains of multiple sclerosis (MS) patients, prompting interest in a possible link. The present study aimed to elucidate the role of ZIKV in the pathogenesis of MS. ZIKV-infected mice with experimental autoimmune encephalomyelitis (EAE) exhibited aggravated EAE symptoms with significant demyelination of the central nervous system (CNS). Moreover, ZIKV infection promoted pathogenic T cell infiltration into the CNS by enhancing the expression of chemokines for C-C motif chemokine receptor 2 (CCR2) in astrocytes, which was dependent on tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling. Propagermanium, a CCR2 inhibitor, prevented ZIKV-induced exacerbation of EAE in mice. These findings highlight the critical role of TRAF6 signaling in the progression of neurological disorders caused by ZIKV infection.
Shibata T, Okabe-Kibe K, Chen H
… +18 more, Yamaguchi K, Koga D, Taoka M, Motoi Y, Sato R, Hsiao HW, Fukui R, Kaneko N, Wang Z, Li Y, Wei W, Cai Z, Furukawa Y, K Nishimura E, Kawano S, Moriyama M, Nakamura S, Miyake K
Int Immunol
· 2026 May · PMID 41332187
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Autoimmune sialadenitis is a hallmark of IgG4-related disease (IgG4-RD) and Sjögren syndrome. The single-stranded RNA sensor TLR7 has been shown as a driver of sialadenitis. Although TLR7 is activated by ssRNA degradatio...Autoimmune sialadenitis is a hallmark of IgG4-related disease (IgG4-RD) and Sjögren syndrome. The single-stranded RNA sensor TLR7 has been shown as a driver of sialadenitis. Although TLR7 is activated by ssRNA degradation products such as nucleosides and oligoribonucleotides, the role of these ligands in sialadenitis development remains unclear. Here, we demonstrate that lysosomal accumulation of endogenous nucleosides is sufficient to drive autoimmune sialadenitis. Loss-of-function genetic variations in the nucleoside transporter SLC29A3 cause lysosomal nucleoside accumulation, leading to constitutive activation of TLR7 and TLR8 in monocytes and macrophages. Consequently, macrophages infiltrate multiple organs in mice and humans. In Slc29a3-/- mice, submandibular glands (SMGs) were impaired in saliva production. SLC29A3-deficiency specifically damaged Aqp5+ acinar and intercalated duct cells in SMGs, while sparing neighboring cells such as ductal and myoepithelial cells. Although macrophages accumulated in both the spleen and SMGs, lymphocyte infiltration and production of chemokines, including CXCL9, CXCL13, and CCL5, occurred selectively in SMGs. In IgG4-RD patients, these chemokines were also produced in SMGs, highlighting parallels between sialadenitis in Slc29a3-/- mice and IgG4-RD. These findings indicate that constitutive TLR7 activation by nucleosides is a key mechanism driving autoimmune sialadenitis.
Ohno Y, Mochizuki M, Kawai K
… +3 more, Goto M, Takahashi R, Ito R
Int Immunol
· 2026 May · PMID 41332185
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Humanized mice are invaluable models for investigating human cell engraftment in vivo post-transplantation. Mice engrafted with human red blood cells (hRBCs) are useful for examining the physiological roles of hRBCs in v...Humanized mice are invaluable models for investigating human cell engraftment in vivo post-transplantation. Mice engrafted with human red blood cells (hRBCs) are useful for examining the physiological roles of hRBCs in vivo, including studies on blood disorders, immune responses, and transfusion-related research. These models hold promise for malaria infection studies and vaccine development. However, engrafted hRBCs in vivo in immunodeficient mice present challenges that must be addressed to establish effective in vivo models. In this study, we explored the rejection mechanisms of hRBCs in immunodeficient NOD/Shi-scid-IL2rγnull (NOG) mice and developed a novel model for long-term RBC engraftment. We observed rapid depletion of fluorescently labeled hRBCs in the liver, but not in other organs, of NOG mice, with Gr-1midCD68+ mouse macrophages playing a significant role in the elimination of hRBCs in the liver. To counteract this, we created thymidine kinase (TK) transgenic (Tg) mice under the human CD68 promoter (NOG-pCD68-TK Tg), which, upon administration of valganciclovir (VGCV), led to the successful depletion of macrophages. Consequently, hRBCs showed significantly prolonged engraftment in NOG-pCD68-TK Tg mice compared to non-Tg mice following macrophage depletion, maintaining engraftment for up to 14 d post-transplantation. This study elucidates the erythrophagocytosis mechanisms of hRBCs in mice and establishes NOG-pCD68-TK Tg mice as a valuable model for the long-term engraftment of hRBCs, potentially advancing in vivo hRBC research.
Int Immunol
· 2026 Apr · PMID 41250890
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The human gastrointestinal tract is a unique mucosal barrier with a tremendous surface area that is subject to continuous exposure to the environment. The immune system must remain poised to protect this organ system fro...The human gastrointestinal tract is a unique mucosal barrier with a tremendous surface area that is subject to continuous exposure to the environment. The immune system must remain poised to protect this organ system from potential pathogens while restraining chronic inflammatory responses that negatively impact physiological functions or facilitate malignancy. Innate lymphocytes emerged as major regulators of gut health through numerous key functions. Recent evidence indicates that these cells are adaptively influenced by specialized microniches, or distinct aggregates of cells that engage in dynamic crosstalk at a microscopic level and integrate signals from the environment to perform specialized functions with regional precision. Here, we explore our current understanding of how microniches in the gut shape the biology of innate lymphocytes, with a focus on an interplay of diet and microbial exposure, selective cell-cell communication networks, and spatiotemporal properties. We also discuss how these microniches may be altered in human diseases or could be harnessed to better protect the gut. Finally, we identify current gaps in knowledge in this rapidly emerging field.
Fasting is known to alter the circulation dynamics of immune cells, including T cells, by shifting them from peripheral tissues to the bone marrow (BM), where they enter a quiescent state to avoid starvation stress and a...Fasting is known to alter the circulation dynamics of immune cells, including T cells, by shifting them from peripheral tissues to the bone marrow (BM), where they enter a quiescent state to avoid starvation stress and acquire apoptosis resistance through upregulation of BCL2. Upon refeeding, these T cells exit the BM and return to circulation. In solid tumors, fasting-refeeding not only affects the trafficking of CD8+ T cells between tumors and their draining lymph nodes (dLNs); but also modulates the antitumor immune response. In this study, we investigated how metformin's antitumor responses are affected by repeated fasting-refeeding cycles. Metformin administration combined with weekly 48-hour fasting showed a synergistic antitumor effect, which was abolished by in vivo depletion of CD8+ T cells. Immunohistofluorescence staining showed that fasting reduced CD8+ T cells in tumors and dLNs while increasing their presence in the BM; refeeding reversed this distribution. Refeeding also increased the expression of Ifng, Gzmb, Tnf, and Tbx21 in tumors. Likewise, Cxcr6, Cxcl16, and Vcam1 expression levels were elevated only upon refeeding. Notably, CXCR6 was exclusively expressed on CD62L- effector memory T cells (TEM). The antitumor effect induced by the combinational therapy was abolished by administration of an anti-VCAM-1 neutralizing antibody. Our findings demonstrate that combining metformin with fasting exerts a synergistic antitumor effect by recruiting CD8+ T cells-relocated to the BM during fasting-back to the tumor during refeeding, facilitated by enhanced VCAM-1 expression on normalized tumor vasculature.
Funakoshi K, Koike T, Ise W
… +5 more, Tai Y, Narazaki M, Kumanogoh A, Inoue T, Kurosaki T
Int Immunol
· 2026 Mar · PMID 41216948
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In a typical immune response, naïve B cells are activated, differentiated into short-lived plasma cells (SLPCs), and then matured into long-lived plasma cells (LLPCs) in the bone marrow. Among three TNF family receptors...In a typical immune response, naïve B cells are activated, differentiated into short-lived plasma cells (SLPCs), and then matured into long-lived plasma cells (LLPCs) in the bone marrow. Among three TNF family receptors (BAFF-R, TACI, and BCMA), BAFF-R and BCMA are known to be crucial for the maintenance of naïve B cells and bone marrow LLPCs, respectively. In contrast, the function of TACI remains unclear, as analysis of global TACI knockout mice suggests the existence of two opposing roles in B and plasma cells. Here, to define the role of TACI during T cell-dependent (TD) immune responses in a B and plasma cell-intrinsic manner, we utilized adoptive transfer experiments employing B cells with a conditional TACI knockout. We show that B cell activation is apparently normal in the absence of TACI, while it is crucial for the expansion of IgM+ and IgG1+ SLPCs and maintenance of their resultant bone marrow LLPCs. Hence, our data suggest that the hyper-B cell activation seen in global TACI knockout mice could be due to an indirect control of BAFF levels or B cell extrinsic anomalies.
Yoshii K, Liu Z, Shimoyama A
… +7 more, Hirayama Y, Iemitsu K, Node E, Hosomi K, Kiyono H, Fukase K, Kunisawa J
Int Immunol
· 2026 Apr · PMID 41216838
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We previously identified Alcaligenes as symbiotic bacteria residing within Peyer's patches and demonstrated that their primary components, lipopolysaccharides, and their active center, lipid A, are excellent adjuvants fo...We previously identified Alcaligenes as symbiotic bacteria residing within Peyer's patches and demonstrated that their primary components, lipopolysaccharides, and their active center, lipid A, are excellent adjuvants for mucosal vaccination. Here, we evaluated the effectiveness of Alcaligenes-derived lipid A as an adjuvant for sublingual immunization, a novel vaccination route. Mice sublingually immunized with Alcaligenes lipid A and ovalbumin (OVA) showed enhanced production of OVA-specific IgA in both the respiratory and gastrointestinal tracts. In addition, increased serum levels of OVA-specific and IgG antibodies were elicited through germinal center reactions in the draining lymph nodes without excessive inflammation at the administration sites. These results demonstrated superior efficacy not previously achieved through other routes of administration (e.g. intranasal, subcutaneous, intramuscular administration) or by existing adjuvants (e.g. CpG-ODN). In addition, sublingual immunization with cholera toxin B subunit (CTB) and lipid A led to an elevated CTB-specific IgG response in the systemic compartment and an elevated IgA response in the intestinal tract, effectively suppressing the diarrhea induced by oral challenge with cholera toxin. Furthermore, immunization with pneumococcal surface protein A (PspA) plus Alcaligenes lipid A elicited strong PspA-specific CD4+ T cell proliferation and Th17 responses, as well as IgA and IgG responses, in both the respiratory tract and the systemic compartment. These effects enhanced pneumococcal clearance in the lungs and subsequent protection against Streptococcus pneumoniae infection. Together, our findings suggest that Alcaligenes-derived lipid A is a potent sublingual vaccine adjuvant with potential efficacy against both respiratory and intestinal infectious diseases.
Biliary tract cancer (BTC) exhibits a poor prognosis and limited responses to current therapeutic strategies. While surgical resection followed by adjuvant S-1 therapy is the standard curative treatment for BTC, long-ter...Biliary tract cancer (BTC) exhibits a poor prognosis and limited responses to current therapeutic strategies. While surgical resection followed by adjuvant S-1 therapy is the standard curative treatment for BTC, long-term postoperative remission is hardly achieved. Therefore, more effective perioperative strategies are urgently needed. Here, we show that an immune-cold tumor microenvironment (TME) in KRAS-mutated BTC correlated with resistance to postoperative adjuvant S-1 therapy. Surgically resected tumor specimens were collected from 31 BTC patients who received adjuvant S-1 therapy after surgery and were subjected to integrated immunogenomic analysis, including multiplexed immunohistochemistry staining and whole-exome sequencing. The analysis revealed a strong correlation between limited CD8⁺ T cell and antigen-presenting cell (APC) infiltration into the TME and KRAS mutations in BTC. In addition, the distances between tumor cells and APCs, as well as between APCs and CD8⁺ T cells, were significantly greater in the TME of KRAS-mutated BTC than in that of KRAS wild-type BTC. These findings indicate that interactions between effector T cells and APCs were impaired in the TME of KRAS-mutated BTC, thereby disrupting antitumor immune responses. Furthermore, wild-type KRAS and abundant CD8⁺ T cells and APCs correlated with a favorable prognosis following adjuvant S-1 therapy for BTC. Altogether, we propose a novel immunogenomic-based biomarker for optimizing perioperative chemotherapy for BTC.
Ohtani M, Fujii H, Watanabe T
… +8 more, Ohara O, Maruya M, Fagarasan S, Hoshii T, Hirao A, Koyasu S, Kubo M, Matsuda S
Int Immunol
· 2026 Mar · PMID 41122976
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The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) regulates various cellular processes, including immune responses. Previous studies have demonstrated that mTORC1 plays a crucial role in B cell differentiation...The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) regulates various cellular processes, including immune responses. Previous studies have demonstrated that mTORC1 plays a crucial role in B cell differentiation and the production of IgM and IgG antibodies in response to foreign antigens. However, its role in steady-state antibody production remains poorly understood. In this study, we found that RaptorB-/- mice, which have a B cell-specific deletion of Raptor (an essential component of mTORC1), retained gut-associated IgA production. Conversely, IgM and IgG subclasses were virtually absent due to the loss of peripheral IgM+ mature B cells. We also found that IgA-producing cells were driven by the gut microbiota and were primarily localized in the intestinal lamina propria of RaptorB-/- mice. Consistently, IgA produced in RaptorB-/- mice was functional in its ability to bind gut bacteria and contributed to maintaining gut microbiota α-diversity, although its repertoire was restricted compared with that of control mice. Our findings demonstrated a distinct population of IgA-producing cells that develop independently of mTORC1 and contribute to gut homeostasis, thereby distinguishing them from conventional IgM- and IgG-producing cells.
Kato Y, Takabayashi T, Shimizu A
… +13 more, Maegawa A, Kato E, Adachi N, Koyama K, Saito K, Yoshida K, Kidoguchi M, Morikawa T, Imoto Y, Sakashita M, Ito M, Kubo M, Fujieda S
Int Immunol
· 2026 Mar · PMID 41060242
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Cells of the innate immune system, specifically Group 2 innate lymphoid cells (ILC2s), play an important role in Type 2 inflammation. However, their involvement in allergic rhinitis remains unclear. Thus, in this study,...Cells of the innate immune system, specifically Group 2 innate lymphoid cells (ILC2s), play an important role in Type 2 inflammation. However, their involvement in allergic rhinitis remains unclear. Thus, in this study, we aimed to clarify the role of ILC2s and acquired immune responses in the onset of allergic rhinitis induced via intranasal mucosal sensitization with antigens in mice. Naive mice were intranasally administered antigens in the short term (4 consecutive days) or long term (21 consecutive days). The number of sneezes, serum-specific immunoglobulin E (IgE) levels, and eosinophil infiltration in the nasal mucosa were subsequently assessed. Short-term intranasal antigen administration to naive mice induced eosinophilic inflammation of the nasal mucosa in an acquired immune-independent and protease- and ILC2-dependent manner. Antigen-independent sneezing was caused by a calcium influx response via transient receptor potential vanilloid channels. In contrast, long-term intranasal mucosal sensitization with antigens led to the onset of allergic rhinitis. Furthermore, increased serum-specific IgE levels and sneezing frequency, as well as significant eosinophilic infiltration, were observed in the nasal mucosa. ILC2s in the nasal mucosa did not proliferate upon short-term stimulation with antigens but proliferated upon long-term stimulation, facilitating acquired immunity and allergic rhinitis onset. Our findings demonstrated that allergic inflammation is induced by the protease/IL-33/ILC2/IL-5 axis during the initiator phase. Acquired immunity induced by long-term sensitization and innate immunity facilitated by short-term sensitization together induce significant allergic inflammation and allergic rhinitis onset.