International Immunology[JOURNAL]
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200 papers
Near-infrared photoimmunotherapy and anti-cancer immunity.
Nakajima K, Ogawa M
Int Immunol · 2024 Feb · PMID 37843836 · Publisher ↗
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 IR...
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.
Metabolic advantages of regulatory T cells dictated by cancer cells.
Kondo M, Kumagai S, Nishikawa H
Int Immunol · 2024 Feb · PMID 37837615 · Publisher ↗
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 lo...
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".
Peripheral helper T cells, mavericks of peripheral immune responses.
Yoshitomi H
Int Immunol · 2024 Jan · PMID 37788648 · Full text
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 periphe...
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.
IL-27 regulates NLRP3 inflammasome activation of MDSCs in experimental Sjögren's syndrome.
Xia X, Long Q, Zha J … +5 more , Jiang T, Guo J, Jiang B, Li X, Yao G
Int Immunol · 2023 Nov · PMID 37756640 · Publisher ↗
Excessive NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation has an important function in the pathogenesis of Sjögren's syndrome (SS). Increased and dysfunctional myeloid-derive...
Excessive NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation has an important function in the pathogenesis of Sjögren's syndrome (SS). Increased and dysfunctional myeloid-derived suppressor cells (MDSCs) promoted SS. However, NLRP3 inflammasome activation of MDSCs in SS and its regulated components are unclear. Splenic MDSCs were purified by immunomagnetic beads and cultured. Western blot was used to assess NLRP3 inflammasomes. Interleukin-1β (IL-1β) and IL-18 were measured using enzyme-linked immunosorbent assay. Here we showed that the NLRP3 inflammasome was activated in non-obese diabetic (NOD) mice with SS-like manifestations. We found that NLRP3 inflammasome activation was augmented in MDSCs of SS mice and NLRP3 inflammasome activation was suppressed in IL-27-deficient NOD mice. Consistent with findings of SS mice in vivo, we observed that NLRP3 inflammasome activation by adenosine triphosphate and lipopolysaccharide was remarkably intensified in MDSCs with IL-27 treatment in vitro. Collectively, our data highlighted that IL-27 regulates NLRP3 inflammasome activation of MDSCs in experimental SS.
Correction to: Lung group 2 innate lymphoid cells differentially depend on local IL-7 for their distribution, activation, and maintenance in innate and adaptive immunity-mediated airway inflammation.
Int Immunol · 2023 Nov · PMID 37738441 · Publisher ↗
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Cytokine signaling in chimeric antigen receptor T-cell therapy.
Kagoya Y
Int Immunol · 2024 Feb · PMID 37591521 · Full text
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...
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.
Mucosal-associated invariant T cells from Clostridioides difficile-infected patients exhibit a distinct proinflammatory phenotype and enhanced cytotoxic activity.
Brauns S, Marquardt I, Thon C … +7 more , Frentzel S, Jakob J, Färber J, Philipsen L, Jänsch L, Link A, Bruder D
Int Immunol · 2023 Nov · PMID 37549964 · Publisher ↗
Mucosal-associated invariant T (MAIT) cells are innate-like T cells mainly found in the mucosa and peripheral blood. We have recently demonstrated that Clostridioides difficile activates MAIT cells in vitro. However, the...
Mucosal-associated invariant T (MAIT) cells are innate-like T cells mainly found in the mucosa and peripheral blood. We have recently demonstrated that Clostridioides difficile activates MAIT cells in vitro. However, their role in the pathogenesis of C. difficile infection (CDI) in human patients remains elusive to date. In this study, we performed comprehensive immunophenotyping of MAIT cells derived from CDI patients and compared their phenotype to that of patients with inflammatory bowel diseases (IBD) and healthy controls. Our study revealed that blood MAIT cells from CDI patients exhibit an interleukin 17a (IL-17a)-dominated proinflammatory phenotype and an increased readiness to synthesize the proinflammatory cytokine interferon γ (IFN-γ) following in vitro re-stimulation. Moreover, the cytotoxic activity of MAIT cells, as measured by surface CD107a and intracellular granzyme B expression, was strongly increased in CDI. Multi epitope ligand cartography (MELC) analysis of intestinal biopsies from CDI patients revealed that MAIT cells exhibit an increased production of granzyme B and increased cytotoxicity compared to the control group. Together with previously published in vitro data from our group, our findings suggest that MAIT cells are functionally involved in the immune response against C. difficile and contribute to the pathogenesis of CDI.
Follicular regulatory T cell subsets in mice and humans: origins, antigen specificity and function.
Sokolova S, Grigorova IL
Int Immunol · 2023 Dec · PMID 37549239 · Publisher ↗
Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both positive and negative regulation of foreign antigen-specific B cell responses, control over autoreactive antibody responses...
Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both positive and negative regulation of foreign antigen-specific B cell responses, control over autoreactive antibody responses and autoimmunity, and B cell class-switching to IgE and allergy development. Studies conducted on mice uncovered various subsets of CXCR5+FoxP3+CD4+ Tfr cells that could differently contribute to immune regulation. Moreover, recent studies of human Tfr cells revealed similar complexity with various subsets of follicular T cells of different origins and immunosuppressive and/or immunostimulatory characteristics. In this review we will overview and compare Tfr subsets currently identified in mice and humans and will discuss their origins and antigen specificity, as well as potential modes of action and contribution to the control of the autoimmune and allergic reactions.
The ligand interactions of B cell Siglecs are involved in the prevention of autoimmunity to sialylated self-antigens and in the quality control of signaling-competent B cells.
Tsubata T
Int Immunol · 2023 Oct · PMID 37504378 · Publisher ↗
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of membrane molecules that recognize sialic acid. Most of them are inhibitory receptors that inhibit immune-cell activation by recognizing sialic aci...
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of membrane molecules that recognize sialic acid. Most of them are inhibitory receptors that inhibit immune-cell activation by recognizing sialic acid as a self-motif. Human B cells express CD22 (also known as Siglec-2), Siglec-5, Siglec-6 and Siglec-10 whereas mouse B cells express CD22 and Siglec-G (ortholog of human Siglec-10). Siglecs recognize both sialylated molecules expressed on the same cell (cis-ligands) and those expressed by other cells (trans-ligands). In Guillain-Barré syndrome (GBS), antibody production to gangliosides (which are sialic acid-containing glycolipids) expressed by neurons plays a pathogenic role. A Siglec-10 variant deficient in recognition of gangliosides is genetically associated with GBS, suggesting that Siglec-10 induces self-tolerance to gangliosides by recognizing gangliosides as trans-ligands. Recognition of the BCR as a cis-ligand by Siglec-G and CD22 suppresses BCR signaling in B-1 cells and conventional B cells, respectively. This signal suppression prevents excess expansion of B-1 cells and is involved in the quality control of signaling-competent B cells by setting a threshold for tonic signaling during B cell development. CD22 recognizes other cis-ligands including CD22 and β7 integrin. Interaction of CD22 with other CD22 molecules induces CD22 clustering that suppresses CD22-mediated signal inhibition upon BCR ligation, and interaction with β7 integrin maintains its function in the gut-homing of B cells. Taken together, interactions of B cell Siglecs with multiple trans- and cis-ligands play important roles in B cell homeostasis and immune responses.
Lung group 2 innate lymphoid cells differentially depend on local IL-7 for their distribution, activation, and maintenance in innate and adaptive immunity-mediated airway inflammation.
Takami D, Abe S, Shimba A … +9 more , Asahi T, Cui G, Tani-Ichi S, Hara T, Miyata K, Ikutani M, Takatsu K, Oike Y, Ikuta K
Int Immunol · 2023 Nov · PMID 37493250 · Publisher ↗
Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 pro...
Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.
NOTCH4 potentiates the IL-13 induced genetic program in M2 alternative macrophages through the AP1 and IRF4-JMJD3 axis.
López-López S, Romero de Ávila MJ, González-Gómez MJ … +5 more , Nueda ML, Baladrón V, Monsalve EM, García-Ramírez JJ, Díaz-Guerra MJM
Int Immunol · 2023 Oct · PMID 37478314 · Publisher ↗
IL-13 signaling polarizes macrophages to an M2 alternatively activated phenotype, which regulates tissue repair and anti-inflammatory responses. However, an excessive activation of this pathway leads to severe pathologie...
IL-13 signaling polarizes macrophages to an M2 alternatively activated phenotype, which regulates tissue repair and anti-inflammatory responses. However, an excessive activation of this pathway leads to severe pathologies, such as allergic airway inflammation and asthma. In this work, we identified NOTCH4 receptor as an important modulator of M2 macrophage activation. We show that the expression of NOTCH4 is induced by IL-13, mediated by Janus kinases and AP1 activity, probably mediated by the IL-13Rα1 and IL-13Rα2 signaling pathway. Furthermore, we demonstrate an important role for NOTCH4 signaling in the IL-13 induced gene expression program in macrophages, including various genes that contribute to pathogenesis of the airways in asthma, such as ARG1, YM1, CCL24, IL-10, or CD-163. We also demonstrate that NOTCH4 signaling modulates IL-13-induced gene expression by increasing IRF4 activity, mediated, at least in part, by the expression of the histone H3K27me3 demethylase JMJD3, and by increasing AP1-dependent transcription. In summary, our results provide evidence for an important role of NOTCH4 signaling in alternative activation of macrophages by IL-13 and suggest that NOTCH4 may contribute to the increased severity of lesions in M2 inflammatory responses, such as allergic asthma, which points to NOTCH4 as a potential new target for the treatment of these pathologies.
Decreased TAX1BP1 participates in systemic lupus erythematosus by regulating monocyte/macrophage function.
Qian T, Huo B, Deng X … +4 more , Song X, Jiang Y, Yang J, Hao F
Int Immunol · 2023 Oct · PMID 37465957 · Publisher ↗
Systemic lupus erythematosus (SLE) involves disorders of innate and adaptive immune pathways. Tax1-binding protein 1 (TAX1BP1) modulates the production of antibodies in B cells and the T-cell cycle by regulating the NF-κ...
Systemic lupus erythematosus (SLE) involves disorders of innate and adaptive immune pathways. Tax1-binding protein 1 (TAX1BP1) modulates the production of antibodies in B cells and the T-cell cycle by regulating the NF-κB signaling pathway. However, the potential association of TAX1BP1 with SLE and its role in monocytes/macrophages have not been fully elucidated. In this study, we utilized whole-exome sequencing (WES) in combination with Sanger sequencing and identified 16 gene mutations, including in TAX1BP1, in an SLE family. TAX1BP1 protein expression with western blotting detection was reduced in SLE patients and correlated with disease activity negatively. Furthermore, RNA sequencing and 4D Label-Free Phosphoproteomic analysis were employed to characterize the transcriptome and phosphoproteome profiles in THP-1 and THP-1-differentiated M1 macrophages with TAX1BP1 knockdown. Silencing of TAX1BP1 in THP-1 and THP-1-differentiated M1 macrophages led to an increase in cluster of differentiation 80 (CD80) expression and differential changes in CD14 and CD16 expression, as assessed by flow cytometry. Additionally, western blot analysis showed that knockdown of TAX1BP1 led to a reduction in TRAF6 and p-p65 in THP-1-differentiated macrophages, with or without lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α stimulation. Taken together, our findings suggest that TAX1BP1 participates in SLE activity by regulating antigen presentation in monocytes and inflammatory responses in M1 macrophages.
Low-dose perinatal supplementation with Enterococcus faecalis increases concentrations of short-chain fatty acids in the offspring but does not protect against allergic asthma.
Arntz JL, Alhasan MM, Datye S … +5 more , Kahhaleh FG, Almousa Y, Barrientos G, Schwiertz A, Conrad ML
Int Immunol · 2023 Oct · PMID 37464466 · Publisher ↗
Childhood allergic asthma is associated with a dysbiotic gut microbiome in early life, and maternal perinatal treatment with probiotics is a potential way alter the infant microbiome, which may improve asthma outcomes. T...
Childhood allergic asthma is associated with a dysbiotic gut microbiome in early life, and maternal perinatal treatment with probiotics is a potential way alter the infant microbiome, which may improve asthma outcomes. This study used a mouse model to examine the effect of maternal supplementation with the probiotic Enterococcus faecalis on faecal short-chain fatty acid (SCFA) concentrations and asthma risk in the offspring. Pregnant/lactating mice were treated daily, from gestation day 6 to postnatal day 21, with an oral suspension of 106, 107 or 108 colony-forming units of a live preparation of the probiotic E. faecalis (Symbioflor®1). At weaning, offspring were subjected to an ovalbumin-induced experimental asthma protocol. Faeces were collected from the mothers and offspring at several different time points to determine SCFA concentrations. It was found that maternal supplementation with E. faecalis did not alter litter size, sex ratio or offspring weight, and was associated with an increase in SCFAs in offspring faeces at weaning and after allergy induction. However, allergic offspring from E. faecalis supplemented mothers showed no difference in asthma severity when compared with allergic offspring from control mothers. In conclusion, although maternal perinatal supplementation with low-dose E. faecalis was associated with increased faecal SCFAs in the offspring, it did not protect against offspring asthma. This is may be because SCFA concentrations were not increased to an immunoprotective level. We recommend that future studies concentrate on probiotic supplementation in high-risk cases, for instance, to repair gut dysbiosis resulting from antibiotic use in pregnant mothers or their infants.
Correction to: Immunogenicity evaluation of viral peptides via nonspecific interactions between anti-peptide IgYs and non-cognate peptides.
Int Immunol · 2023 Nov · PMID 37433024 · Publisher ↗
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Contributions of the N-terminal flanking residues of an antigenic peptide from the Japanese cedar pollen allergen Cry j 1 to the T-cell activation by HLA-DP5.
Kusano S, Ueda S, Oryoji D … +16 more , Toyoumi A, Hashimoto-Tane A, Kishi H, Hamana H, Muraguchi A, Jin H, Arase H, Miyadera H, Kishikawa R, Yoshikai Y, Yamada H, Yamamoto K, Nishimura Y, Saito T, Sasazuki T, Yokoyama S
Int Immunol · 2023 Sep · PMID 37418020 · Full text
Cry j 1 is a major allergen present in Japanese cedar (Cryptomeria japonica) pollens. Peptides with the core sequence of KVTVAFNQF from Cry j 1 ('pCj1') bind to HLA-DP5 and activate Th2 cells. In this study, we noticed t...
Cry j 1 is a major allergen present in Japanese cedar (Cryptomeria japonica) pollens. Peptides with the core sequence of KVTVAFNQF from Cry j 1 ('pCj1') bind to HLA-DP5 and activate Th2 cells. In this study, we noticed that Ser and Lys at positions -2 and -3, respectively, in the N-terminal flanking (NF) region to pCj1 are conserved well in HLA-DP5-binding allergen peptides. A competitive binding assay showed that the double mutation of Ser(-2) and Lys(-3) to Glu [S(P-2)E/K(P-3)E] in a 13-residue Cry j 1 peptide (NF-pCj1) decreased its affinity for HLA-DP5 by about 2-fold. Similarly, this double mutation reduced, by about 2-fold, the amount of NF-pCj1 presented on the surface of mouse antigen-presenting dendritic cell line 1 (mDC1) cells stably expressing HLA-DP5. We established NF-pCj1-specific and HLA-DP5-restricted CD4+ T-cell clones from HLA-DP5 positive cedar pollinosis (CP) patients, and analyzed their IL-2 production due to the activation of mouse TG40 cells expressing the cloned T-cell receptor by the NF-pCj1-presenting mDC1 cells. The T-cell activation was actually decreased by the S(P-2)E/K(P-3)E mutation, corresponding to the reduction in the peptide presentation by this mutation. In contrast, the affinity of NF-pCj1·HLA-DP5 for the T-cell receptor was not affected by the S(P-2)E/K(P-3)E mutation, as analyzed by surface plasmon resonance. Considering the positional and side-chain differences of these NF residues from previously reported T-cell activating sequences, the mechanisms of enhanced T-cell activation by Ser(-2) and Lys(-3) of NF-pCj1 may be novel.
Systemic immunometabolism and responses to vaccines: insights from T and B cell perspectives.
Nettelfield S, Yu D, Cañete PF
Int Immunol · 2023 Dec · PMID 37330692 · Full text
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 malnouris...
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.
A CCR4 antagonist attenuates atopic dermatitis-like skin inflammation by inhibiting the recruitment and expansion of Th2 cells and Th17 cells.
Sato M, Matsuo K, Susami Y … +8 more , Yamashita A, Hayasaka H, Hara Y, Nishiwaki K, Oiso N, Kawada A, Otsuka A, Nakayama T
Int Immunol · 2023 Sep · PMID 37279584 · Publisher ↗
CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upre...
CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c+ dendritic cells (DCs) and CD4+ T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.
Foxp3 and Bcl6 deficiency synergistically induces spontaneous development of atopic dermatitis-like skin disease.
Tai Y, Sakaida Y, Kawasaki R … +6 more , Kanemaru K, Akimoto K, Brombacher F, Ogawa S, Nakamura Y, Harada Y
Int Immunol · 2023 Sep · PMID 37279329 · Publisher ↗
Atopic dermatitis (AD) is a common chronic skin disease caused by immune dysfunction, specifically the hyperactivation of Th2 immunity. AD is a complex disease with multiple factors contributing to its development; howev...
Atopic dermatitis (AD) is a common chronic skin disease caused by immune dysfunction, specifically the hyperactivation of Th2 immunity. AD is a complex disease with multiple factors contributing to its development; however, the interaction between these factors is not fully understood. In this study, we demonstrated that the conditional deletion of both the forkhead box p3 (Foxp3) and B-cell lymphoma 6 (Bcl6) genes induced the spontaneous development of AD-like skin inflammation with hyperactivation of type 2 immunity, skin barrier dysfunction, and pruritus, which were not induced by the single deletion of each gene. Furthermore, the development of AD-like skin inflammation was largely dependent on IL-4/13 signaling but not on immunoglobulin E (IgE). Interestingly, we found that the loss of Bcl6 alone increased the expression of thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33 in the skin, suggesting that Bcl6 controls Th2 responses by suppressing TSLP and IL-33 expression in epithelial cells. Our results suggest that Foxp3 and Bcl6 cooperatively suppress the pathogenesis of AD. Furthermore, these results revealed an unexpected role of Bcl6 in suppressing Th2 responses in the skin.
Memory B cell differentiation from germinal centers.
Inoue T
Int Immunol · 2023 Dec · PMID 37232558 · Publisher ↗
Establishment of humoral immune memory depends on two layers of defense: pre-existing antibodies secreted by long-lived plasma cells; and the antibodies produced by antigen-reactivated memory B cells. Memory B cells can...
Establishment of humoral immune memory depends on two layers of defense: pre-existing antibodies secreted by long-lived plasma cells; and the antibodies produced by antigen-reactivated memory B cells. Memory B cells can now be considered as a second layer of defense upon re-infection by variant pathogens that have not been cleared by the long-lived plasma cell-mediated defense. Affinity-matured memory B cells are derived from the germinal center (GC) reaction, but the selection mechanism of GC B cells into the memory compartment is still incompletely understood. Recent studies have revealed the critical determinants of cellular and molecular factors for memory B cell differentiation from the GC reaction. In addition, the contribution of antibody-mediated feedback regulation to B cell selection, as exemplified by the B cell response upon COVID-19 mRNA vaccination, has now garnered considerable attention, which may provide valuable implications for future vaccine design.
Computer model of IL-6-dependent rheumatoid arthritis in F759 mice.
Yamamoto R, Yamada S, Atsumi T … +14 more , Murakami K, Hashimoto A, Naito S, Tanaka Y, Ohki I, Shinohara Y, Iwasaki N, Yoshimura A, Jiang JJ, Kamimura D, Hojyo S, Kubota SI, Hashimoto S, Murakami M
Int Immunol · 2023 Sep · PMID 37227084 · Publisher ↗
The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the i...
The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the infiltration of immune cells into the joints of F759 mice. The result is a disease that resembles human rheumatoid arthritis. However, the kinetics and regulatory mechanisms of how augmented transcriptional activation by STAT3 and NF-κB leads to F759 arthritis is unknown. We here show that the STAT3-NF-κB complex is present in the cytoplasm and nucleus and accumulates around NF-κB binding sites of the IL-6 promoter region and established a computer model that shows IL-6 and IL-17 (interleukin 17) signaling promotes the formation of the STAT3-NF-κB complex followed by its binding on promoter regions of NF-κB target genes to accelerate inflammatory responses, including the production of IL-6, epiregulin, and C-C motif chemokine ligand 2 (CCL2), phenotypes consistent with in vitro experiments. The binding also promoted cell growth in the synovium and the recruitment of T helper 17 (Th17) cells and macrophages in the joints. Anti-IL-6 blocking antibody treatment inhibited inflammatory responses even at the late phase, but anti-IL-17 and anti-TNFα antibodies did not. However, anti-IL-17 antibody at the early phase showed inhibitory effects, suggesting that the IL-6 amplifier is dependent on IL-6 and IL-17 stimulation at the early phase, but only on IL-6 at the late phase. These findings demonstrate the molecular mechanism of F759 arthritis can be recapitulated in silico and identify a possible therapeutic strategy for IL-6 amplifier-dependent chronic inflammatory diseases.
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