International immunology最新文献

Photodynamic therapy (PDT), a local cancer treatment using photosensitizers, has been reported to enhance antitumor immune responses by inducing immunogenic cell death. Although several studies have demonstrated the synergistic antitumor effects of PDT and immune checkpoint blockage (ICB), the detailed underlying mechanisms remain poorly understood. In this study, we investigated the immunological effects of PDT with talaporfin (Tal-PDT), a clinically approved photosensitizer, using bilateral tumor-bearing mouse models. Treatment with Tal-PDT on the tumor on one side of the mouse resulted in tumor growth inhibition on the untreated opposite side. This phenomenon, accompanied by tumor antigen-specific immune reactions, is indicative of an abscopal effect. When combined with anti PD-L1 antibody, synergistic antitumor effects were observed on both the laser-treated and untreated sides. Mechanistically, Tal-PDT enhanced the induction of XCR-1+ dendritic cells in the proximal draining lymph node likely through the induction of ferroptosis in tumor cells. This, in turn, led to the systemic generation of precursor-exhausted CD8+ T cells. Moreover, talaporfin was selectively incorporated into tumor cells rather than into tumor-infiltrating T cells in vivo, leading to targeted tumor killing while preserving T cells. These beneficial effects of Tal-PDT on antitumor immunity collectively enhance ICB cancer immunotherapy. Our study demonstrates the potential of combining Tal-PDT with ICB therapy for clinical applications.

Systemic lupus erythematosus is a systemic autoimmune disease characterized by the production of autoantibodies and damage to multiple organs. Glomerulonephritis, a manifestation involving glomerular deposition of immune complexes and complement components, significantly contributes to disease morbidity. Although an endosomal single-stranded RNA sensor [Toll-like receptor 7 (TLR7)] is known to drive glomerulonephritis by promoting autoantibody production in B cells, the contribution of macrophage TLR7 responses to glomerulonephritis remains poorly understood. Here, we have examined Tlr7‒/‒ NZBWF1 (New Zealand Black/New Zealand White F1) mice and found that TLR7 deficiency ameliorates lupus nephritis by abolishing autoantibody production against RNA-associated antigens, C3 deposition, and macrophage accumulation in glomeruli. Furthermore, TLR7 signaling increased CD31 expression on glomerular endothelial cells and Ly6Clow macrophages but not on T and B cells, suggesting that CD31 mediates TLR7-dependent migration of monocytes into glomeruli. Compared to their splenic counterparts, glomerular macrophages produced IL-1β in a TLR7-dependent manner. In addition, single-cell RNA sequencing of glomerular macrophages revealed that TLR7 signaling induced expression of lupus-associated genes, including those encoding Chitinase 3 like 1, ferritin heavy chain 1, IKKε, and complement factor B (CfB). Although serum CfB did not increase in NZBWF1 mice, TLR7-dependent CfB protein expression was detected in glomerular macrophages. In addition, TLR7 signaling promoted C3 cleavage and deposition predominantly on mesangial cells. These findings suggest that TLR7 responses in glomerular macrophages accelerate the progression of glomerulonephritis in NZBWF1 mice.

The cancer driver mutation L265P MyD88 is found in approximately 30% of cases in the activated B cell-like subgroup of diffuse large B cell-like lymphoma (ABC DLBCL). L265P MyD88 forms a complex with TLR9 and IgM, referred to as the My-T-BCR complex, to drive proliferation. We here show that the B cell surface molecules CD19 and CD20 enhance proliferation mediated by the My-T-BCR complex. Using the interleukin 3 (IL-3)-dependent Ba/F3 line transduced to express the IgM complex (IgM, CD79a, and CD79b) and TLR9, we observed proliferation in the presence of anti-IgM antibody and the TLR9 ligand CpG-B. TLR9 was constitutively associated with IgM and L252P MyD88. CD19 promoted proliferation with anti-IgM and CpG-B specifically in L252P MyD88-expressing Ba/F3 cells, while CD20 enhanced the proliferation in both wild-type- and L252P MyD88-expressing Ba/F3 cells. Additionally, CD20 uniquely enabled IgM-mediated proliferation in L252P MyD88-expressing Ba/F3 cells. Although CpG-B was not required for this proliferation, TLR9 expression remained indispensable. In the ABC DLBCL line TMD8, anti-IgM antibody-mediated growth was impaired by the lack of CD20 and CD19 or of TLR9. Mechanistically, CD19 promoted IgM-dependent AKT phosphorylation, whereas CD20 increased expression of cell surface IgM, thereby enhancing the formation of the IgM-TLR9 complex. These findings suggest that CD19 and CD20 differentially contribute to the proliferation driven by the My-T-BCR complex.

Ten-eleven translocation (TET) proteins are dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. In the "passive" (replication-dependent) DNA demethylation pathway, sequential oxidation reactions by TETs are essential and modified cytosines (C) are diluted at each cycle of DNA replication. In the "active" (replication-independent) DNA demethylation pathway, both thymine DNA glycosylase (TDG) and TETs play important roles. TDG removes 5fC and 5caC from 5fC:G and 5caC:G base pairs and these modified bases are replaced by unmodified C via base excision repair. Through epigenetic regulation of DNA demethylation, TETs and TDG are involved in cell development, differentiation, and homeostasis. The interplay between TDG and TETs is involved in embryo development, stem cell differentiation, neural development, immune responses, and tumorigenesis. Loss-of-function mutations of TET proteins in immune cells are associated with a variety of abnormalities, including inflammation, cancer, and clonal hematopoiesis, a condition related to aging. Loss of TETs also has a significant impact on the plasticity and differentiation of T cells, which contributes to inflammation and cancer. In this review, we describe recent findings in functions of TETs in T cell plasticity and differentiation and the TET-TDG axis in selected biological processes.

Long COVID, or post-acute sequelae of COVID-19 (PASC), represents a major global health challenge, with its underlying mechanisms remaining poorly understood despite substantial research and clinical trials. This study investigates the role of the interferon (IFN) axis in the pathogenesis of PASC, drawing parallels to systemic lupus erythematosus (SLE). The potential pathogenic role of IFNs was detected by meta-analyses of mRNA sequencing data comparing PASC patients to healthy controls. We analyzed serum samples from 39 PASC patients and found significant correlations among multiple IFN sub types, including IFN alpha-2, beta, gamma, lambda-1, and lambda-2/3. The biological activity of IFNs in the serum was positively correlated with levels of both total and type III IFNs. Notably, we detected the widespread presence of anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies in these patients, with anti-dsDNA levels showing a strong correlation with IFN activity. On the basis of these findings, we propose a hypothetical autoimmune pathogenesis for PASC highlighting the crucial role of IFN signaling.

Intestinal bacteria play a critical role in the regulation of the host immune system and an imbalance in the intestinal bacterial composition induces various host diseases. Therefore, maintaining a balance in the intestinal bacterial composition is crucial for health. Immunoglobulin A (IgA), produced through T cell-dependent and T cell-independent (TI) pathways, is essential for host defense against pathogen invasion and maintaining the balance of intestinal symbiotic bacteria. Interleukin (IL)-5 is constitutively produced by Group 2 innate lymphoid cells (ILC2s) and plays a critical role in the survival and proliferation of B cells and eosinophils. Here, we show the role of IL-5-producing ILC2s in intestinal TI IgA production at steady state using T cell receptor α deficient mice. In this mouse model, ILC2s increased fecal TI IgA levels in a non-inflammatory state in an IL-5-dependent manner. The administration of recombinant IL-33 (rIL-33) increased the amount of TI IgA production, accompanied by an increase in the number of IL-5-producing ILC2s in the large intestine. In addition, rIL-33 treatment increased IL-5-dependent IgA+ cells in isolated lymphoid follicles, the site of TI IgA production. Furthermore, eosinophils recruited by ILC2s were required for the maximal production of IgA in the TI pathway. Moreover, IL-5 increased the frequency of TI IgA-binding intestinal bacteria and was involved in the maintenance of intestinal bacterial composition. These findings indicate that IL-5-producing ILC2s together with eosinophils contribute to TI IgA production. In addition to their role in TI IgA production, IL-5-producing ILC2s may contribute to the homeostasis of intestinal commensal bacteria.

Periodontitis, a chronic inflammatory disease of periodontal tissue, is often associated with a group of pathogenic bacteria known as the "red complex", including Tannerella forsythia. Previous papers showed that T. forsythia induces many kinds of inflammatory cytokines including interleukin (IL)-1β regulated by inflammasome activation. However, the physiological function of periodontitis and the mechanism to induce inflammasome activation by T. forsythia infection are poorly understood. In this study, we demonstrate that the Nod-like receptor pyrin domain containing 3 (NLRP3) and caspase-4 are essential for inflammasome activation by T. forsythia infection, playing a crucial role in IL-1β maturation in THP-1 cells. We also showed that the knockout of ASC or Gasdermin D suppresses pyroptotic cell death. Moreover, co-immunoprecipitation assays confirmed the formation of a complex involving caspase-4, NLRP3, and ASC following T. forsythia infection. Additionally, reactive oxygen species production was identified as a key factor in caspase-4-mediated NLRP3 inflammasome activation by T. forsythia infection. These results enhance our understanding of inflammasome activation in response to T. forsythia infection and provide new insights into the pathogenic mechanisms of periodontitis.

The pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has threatened human health worldwide. Among protective immune reactions, T cell responses are diverse among individuals, which is related to the differences in severity. A T cell subset, regulatory T (Treg) cells, is crucial for limiting excessive immune responses. If SARS-CoV-2-specific Tregs are developed during infection, they may counteract antiviral immunity and cause severe symptoms. To address this possibility, we conducted single-cell TCR-RNA-sequencing of peripheral blood mononuclear cells from convalescent Coronavirus disease 2019 (COVID-19) patients. Among 13 donors, one with severe symptoms had substantially more FOXP3-expressing Treg clonotypes activated in the presence of SARS-CoV-2 virion or other major antigen proteins. To define the reactivity of these Treg clonotypes, 15 highly expanded Treg clonotypes were reconstituted into reporter cells and stimulated with 27 distinct peptide pools that cover all SARS-CoV-2 proteins. However, none of these clonotypes react to any SARS-CoV-2 antigens. Instead, the reporter cells expressing one TCR clonotype (23599) were activated in the presence of Epstein-Barr virus-transformed B cells without adding exogenous antigens. Furthermore, 23599 TCR-expressing cells were activated by non-transformed naïve syngeneic B cells in a DQA1*03:03-DQB1*04:01-dependent manner, suggesting that clonotype 23599 may be autoreactive. This Treg clonotype, 23599, was also detected in a public TCR database and significantly expanded in COVID-19 patients compared to healthy donors. These results suggest that SARS-CoV-2 is not the dominant antigen inducing Treg cells during infection.

Since the first approval of an immune checkpoint inhibitor, we have witnessed the clinical success of cancer immunotherapy. Adoptive T-cell therapy with chimeric antigen receptor T (CAR-T) cells has shown remarkable efficacy in hematological malignancies. Concurrently with these successes, the cancer immunoediting concept that refined the cancer immunosurveillance concept underpinned the scientific mechanism and reason for past failures, as well as recent breakthroughs in cancer immunotherapy. Now, we face the next step of issues to be solved in this field, such as tumor heterogeneity, the tumor microenvironment, the metabolism of tumors and the immune system, and personalized approaches for patients, aiming to expand the population benefitted by the therapies.

Immune memory has long been considered a function specific to adaptive immune systems; however, adaptive immune memory alone has not fully explained the mechanism by which vaccines exert their protective effects against nontarget pathogens. Recently, trained immunity, in which human monocytes vaccinated with bacillus Calmette-Guérin become highly responsive to pathogens other than Mycobacterium tuberculosis, has been reported. However, a phenomenon called endotoxin tolerance is also known, in which monocyte responsiveness is attenuated after the first lipopolysaccharide stimulation. These phenomena represent an altered innate immune response after the initial exposure to the stimulus, indicating that memories are formed in the innate immune system. In this review, we discuss trained immunity and endotoxin tolerance, known as innate immune memory, and innate immune memory formation by mRNA vaccines, which have been newly used in the coronavirus disease 2019 (COVID-19) pandemic and are considered important vaccine modalities in the future.