International immunology最新文献

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.

Several mesenchymal cell populations are known to regulate intestinal stem cell (ISC) self-renewal and differentiation. However, the influences of signaling mediators derived from mesenchymal cells other than ISC niche factors on epithelial homeostasis remain poorly understood. Here, we show that host and microbial metabolites, such as taurine and gamma-aminobutyric acid (GABA), act on PDGFRαhigh Foxl1high sub-epithelial mesenchymal cells to regulate their transcription. In addition, we found that CXC chemokine ligand 12 (CXCL12) produced from Foxl1high sub-epithelial mesenchymal cells induces epithelial cell cycle arrest through modulation of the mevalonate-cholesterol synthesis pathway, which suppresses tumor progression in ApcMin/+ mice. We identified that Foxl1high sub-epithelial cells highly express CXCL12 among colonic mesenchymal cells. Foxl1-cre; Cxcl12f/f mice showed an increased number of Ki67+ colonic epithelial cells. CXCL12-induced Ca2+ mobilization facilitated phosphorylation of AMPK in intestinal epithelial cells, which inhibits the maturation of sterol regulatory element-binding proteins (SREBPs) that are responsible for mevalonate pathway activation. Furthermore, Cxcl12 deficiency in Foxl1-expressing cells promoted tumor development in the small and large intestines of ApcMin/+ mice. Collectively, these results demonstrate that CXCL12 secreted from Foxl1high mesenchymal cells manipulates intestinal epithelial cell metabolism, which links to the prevention of tumor progression in ApcMin/+ mice.

Basic-leucine zipper transcription factor ATF-like (BATF) and interferon regulatory factor 4 (IRF4) are crucial transcription factors for the generation of cytotoxic effector and memory CD8+ T cells. JunB is required for expression of genes controlled by BATF and IRF4 in CD4+ T cell responses, but the role of JunB in CD8+ T cells remains unknown. Here, we demonstrate that JunB is essential for cytotoxic CD8+ T cell responses. JunB expression is transiently induced, depending on the T cell receptor signal strength. JunB deficiency severely impairs the clonal expansion of effector CD8+ T cells in response to acute infection with Listeria monocytogenes. Junb-deficient CD8+ T cells fail to control transcription and chromatin accessibility of a specific set of genes regulated by BATF and IRF4, resulting in impaired cell survival, glycolysis, and cytotoxic CD8+ T cell differentiation. Furthermore, JunB deficiency enhances the expression of co-inhibitory receptors, including programmed cell death 1 (PD-1) and T cell immunoglobulin mucin-3 (TIM3) upon activation of naive CD8+ T cells. These results indicate that JunB, in collaboration with BATF and IRF4, promotes multiple key events in the early stage of cytotoxic CD8+ T cell responses.

Translocator protein (TSPO) is a mitochondrial outer membrane protein expressed on a variety of immune cells, including macrophages, dendritic cells, and T cells, in addition to neurons and steroid-producing cells. Previous studies of TSPO ligands have suggested that TSPO is involved in multiple cellular functions, including steroidogenesis, immunomodulation, and cell proliferation. Currently, there are limited reports on the effects of TSPO or TSPO ligands on T cell-mediated immune responses. Here, we investigated the involvement of TSPO/TSPO ligand in T cell responses using a 2,4-dinitro-1-fluorobenzene (DNFB)-induced contact hypersensitivity (CH) model. Treatment with Ro5-4864, a TSPO ligand, during DNFB sensitization reduced the number and activation status of CD4+ and CD8+ T cells in draining lymph nodes and alleviated skin inflammation after DNFB challenge. Adoptive transfer of Ro5-4864-treated mouse-derived DNFB-sensitized T cells to naive mice inhibited CH responses after DNFB challenge. Ro5-4864-treated sensitized T cells showed lower proliferative responses when stimulated with DNFB-pulsed antigen-presenting cells compared to control-treated sensitized T cells. Ro5-4864 also suppressed cell proliferation, as well as adenosine triphosphate and lactate production, during T cell activation. Moreover, the inhibitory effects of Ro5-4864 on T cell responses were conserved in TSPO-deficient cells. Our results suggest that Ro5-4864 inhibits CH responses by suppressing energy metabolism, at least via glycolysis, to reduce the T cell primary response in a TSPO-independent manner.

In systemic lupus erythematosus (SLE), the production of autoantibodies is a crucial characteristic, and B cells play a significant role in its pathogenesis. B cells are the immune cells most associated with the genetic predispositions of SLE, and recent clinical studies showing that anti-CD19 chimeric antigen receptor (CAR)-T cell therapy induces drug-free remission have underscored the importance of B cells in SLE. Meanwhile, various B-cell subsets exist across different stages of differentiation, from naive B cells to plasma cells, and identifying the important subpopulations within SLE remains a critical future challenge. Years of B-cell repertoire analyses have revealed the importance of polyreactive B-cell receptors (BCRs) and autoantibodies that react to various self-antigens and microbial antigens. Particularly, memory B cells with polyreactive BCRs, which play a crucial role in biological defense during the fetal stage, are characteristically differentiated in SLE. Type I interferon-mediated expression of CXCL13 and IL-21 in CD4+ T cells is associated with the development of polyreactive memory B cells. The expansion of the polyreactive B-cell repertoire, vital for defending against infections such as viruses, may exert an intrinsic function in SLE.

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 function 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 subtypes, 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. Based on these findings, we propose a hypothetical autoimmune pathogenesis for PASC highlighting the crucial role of IFN signaling.

In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that the translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic [e.g. cyclic GMP-AMP synthase (cGAS), retinoic acid-inducible gene I (RIG-I)-like receptors], and endolysosomal (Toll-like receptor 7, 9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease.

CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and the increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in the CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single-cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active-stage SLE patients with renal manifestation. Meanwhile, the effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive-stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.

Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ programmed cell death protein 1 (PD-1)+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant pro-inflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions, including autoimmunity, and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, as well as autoimmune and chronic inflammatory diseases, and it provides a novel therapeutic clue.