International immunology最新文献

Toll-like receptor 7 (TLR7) is an endosomal sensor that responds to both pathogen-derived and self-derived single-stranded RNA (ssRNA). Responses of TLR7 to self-derived ssRNA have been implicated in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). TLR7 antagonists and inhibitory anti-TLR7 monoclonal antibodies (mAbs) can protect lupus-prone NZBWF1 mice from lethal nephritis. However, less is known about TLR7 dependence and activation in human SLE, as both TLR7 and TLR8 respond to ssRNA in humans. Here, we analyzed public databases and found that TLR7 gene signature scores were consistently elevated across datasets, races, and SLEDAI scores compared to TLR8, suggesting a deeper involvement of TLR7 in SLE pathogenesis. To specifically inhibit human TLR7 responses, we developed inhibitory mAbs against human TLR7. Utilizing an inhibitory clone, we generated the humanized mAb, DS-7011a. DS-7011a effectively inhibited TLR7-mediated responses in plasmacytoid dendritic cells (pDCs) and B cells. Furthermore, DS-7011a was internalized in a TLR7-dependent manner and accumulated in B cells, pDCs, conventional dendritic cells (cDCs), and monocytes/macrophages. In this study, we describe the generation and preclinical development of DS-7011a, which has the potential to be a therapeutic option for the treatment of SLE.

The T-cell receptor (TCR) repertoire is a valuable source of information that reflects an individual's immune status and infection history. However, due to the exceptional diversity and complexity of the TCR repertoire, predicting its functional properties remains a challenging task. This review summarizes recent advances in protein language models (PLMs), which apply natural language processing techniques to protein sequences, focusing specifically on TCR repertoire analysis. We begin by outlining the biological basis of the TCR repertoire and its current clinical applications. We then describe the methods used for representing TCR data and the training procedures of the corresponding PLMs. PLMs capture context-dependent features from large unlabeled TCR datasets and achieve high generalization performance even with limited labeled data through transfer learning. In this respect, PLMs offer significant advantages over conventional sequence representation methods. We highlight antigen specificity prediction as a key application, comparing supervised deep learning models with PLM-based approaches. While employment of PLMs is promising, TCR repertoire analysis still faces challenges such as data scarcity, bias, and lack of paired-chain information. Addressing these challenges requires rigorous dataset optimization, integration, and augmentation strategies. Future advances will require better interpretation of the representations learned by PLMs and the development of multimodal approaches that integrate structural information. These advances could enable several clinical applications, including disease diagnosis, vaccine development, and personalized immune profiling.

The gut microbiota plays an integral role in maintaining health and regulating various host functions, including immune responses. Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic approach to restore gut microbial balance. Although widely recognized for its efficacy in treating ulcerative colitis (UC), FMT is now being investigated as an adjuvant therapy to enhance the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment. This review summarizes the clinical applications of FMT in UC treatment and its potential role in cancer immunotherapy. FMT exhibits varying degrees of efficacy in the treatment of UC, with differences in outcomes attributed to variations in administration methods and donor selection. In cancer therapy, FMT has demonstrated the potential to improve ICI responses, particularly in patients with melanoma. However, its effects on other cancers remain unclear. Although FMT holds promise for UC and cancer immunotherapy, challenges such as inconsistent clinical outcomes and methodological variations persist. Standardized protocols and mechanistic studies are crucial to optimize FMT-based therapeutic strategies, and further research is required to establish its efficacy under diverse clinical conditions.

Vaccines effectively stimulate protective immune responses in healthy individuals, but the precise roles of germinal center (GC) and follicular helper T (TFH) cells in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine responses are not fully understood. This study used a conditional loss-of-function mouse model to investigate antibody responses to the Wuhan spike protein, specifically eliminating newly developed TFH cells during either the primary or memory phase. Our findings demonstrated that TFH-mediated GC responses are essential for primary vaccination. However, after booster immunization, memory B-cell responses were effectively regulated through extrafollicular mechanisms, independent of TFH cells. Ablating IL-4 receptor signaling in B cells attenuated antibody production in both the primary and memory phases, highlighting the critical role of IL-4 for optimal humoral immunity. We identified a unique population of IL-4-expressing memory T (IL-4+Tm) cells, characterized by CD27, GATA3, and IRF4 expression, that is strongly associated with these extrafollicular memory B-cell responses, capable of neutralizing SARS-CoV-2 variants. Furthermore, Omicron-based booster immunization recovered the immunity against emerging variants under TFH-deficient conditions. These results suggest that IL-4+Tm cells are an alternative pathway to sustain memory responses when GC function is impaired, particularly in immunocompromised states. Our study advances the understanding of memory T-cell-mediated humoral responses to SARS-CoV-2, offering insights for future vaccine strategies.

B cells play a critical role in tumor immunity, with their presence associated with improved prognosis in various cancers, including endometrial cancer (EC). However, the nature of the B-cell response within the tumor microenvironment (TME) remains incompletely understood. In this study, we conducted single-cell analyses of B cells and CD4+ T cells in the TME of EC. We found that the TME of EC harbored abundant plasmablasts and plasma cells (PCs), which were rare in normal endometria. PCs primarily expressed either IgG or IgA, and a high abundance of IgG in TME was associated with better overall survival. B-cell receptor (BCR) repertoire analysis revealed a clonal expansion of IgG+ B cells, coinciding with an increased presence of T follicular helper (Tfh) cells in the TME. Notably, Tfh cells shared T-cell receptor clones with cycling CD4+ T cells, indicating local proliferation. BCR repertoire analysis also suggested that IgG+ PCs differentiate from IFN-responding B cells and double-negative B cells in the TME. Additionally, recombinant oligoclonal IgG antibodies were found to recognize antigens expressed by tumor cells as well as normal endometrial cells. Collectively, our study shows that the clonal expansion of IgG+ B cells, along with the Tfh cell response, is associated with a better outcome in EC.

All-trans retinoic acid (atRA), the bioactive component of vitamin A, plays a pivotal role in various biological processes. atRA, essential for embryonic development and immune functions, primarily mediates its regulatory effects by interacting with the nuclear receptor RARα (retinoic acid receptor α). atRA-bound RARα enters the nucleus and forms a heterodimer with RXR (retinoid X receptor). This heterodimer can then interact with various transcription factors to form regulatory complexes that influence gene expression. While the role of atRA in regulating the type 2 immune response has been studied, further exploration into its specific involvement in Th2 cell differentiation is necessary to fully elucidate underlying mechanisms and assess its therapeutic potential. Our study shows that atRA suppressed the Th2 phenotype by downregulating type 2 transcription factors such as Spi1 and cMaf, without altering Gata3 expression. atRA also reduced IL-4 and IL-13 production, while enhancing IL-5 expression, potentially through upregulation of Gfi1. atRA increased the Gfi1 recruitment to the Il4 and Il13 promoters, along with the common enhancer Ecr (evolutionarily conserved region). RARα, which is typically an inducer of Il4 and Il13, was observed to decrease recruitment to these loci in atRA-treated Th2 cells. Comparative gene expression analysis revealed a reduction in inflammatory responses in atRA-treated Th2 cells. Furthermore, these cells exhibited a negative correlation with epigenetic modifications and nuclear receptor activity among other biological processes. Collectively, our findings suggest that atRA can effectively suppress the Th2 phenotype in vitro, through the regulation of key type 2 transcription factors and pathways, indicating its potential therapeutic implications for limiting type 2 immune responses.

Three-prime repair exonuclease 1 (TREX1) is the major 3' to 5' DNA exonuclease in mammals and plays an essential role in preserving immune homeostasis by controlling cytosolic DNA sensing. By degrading excess self and foreign DNA, TREX1 limits aberrant activation of the cGAS-STING (cyclic GMP-AMP synthase - stimulator of interferon genes) pathway and downstream type I interferon responses. Loss-of-function mutations in TREX1 underlie a spectrum of interferon-driven autoimmune and autoinflammatory syndromes, demonstrating its role as a key regulator of immune tolerance. Beyond autoimmunity, recent discoveries have uncovered critical roles for TREX1 in shaping tumor immunogenicity and modulating antiviral defense through regulation of DNA-sensing pathways. In this review, we summarize current insights into the evolutionary origin, structural mechanisms, and functional repertoire of TREX1 in innate immunity. We further discuss how dysregulation of TREX1 contributes to disease and highlight emerging strategies to therapeutically modulate TREX1 activity in cancer and interferonopathies.

The role of the thyroid hormone receptor beta (TR-β) in the immune system remains poorly understood; although its effect on TGF-β signaling has been reported in nonimmune systems. Here, we report that Thrb is highly expressed in pathogenic CD4+ T cells that infiltrate the central nervous system during experimental autoimmune encephalomyelitis (EAE), and Thrb is exclusively expressed in IL-17-producing CD4+ T cells (Th17 cells) that develop both in vitro or in vivo. Sobetirome, a selective TR-β agonist, promoted pathogenic Th17 differentiation and IL-17 production in the presence of exogenous IL-1β. Conversely, small interfering RNA (siRNA)-mediated silencing of TR-β reduced IL-17 production, further supporting a T cell-intrinsic role of TR-β. Because C75, an inhibitor of de novo lipogenesis, blocked Th17 cell differentiation by sobetirome, the influence of TR-β signaling on Th17 cell induction is likely to act via a de novo lipogenesis-dependent mechanism. Furthermore, blocking TR-βexpression by siRNA changed the balance of IL-10/IL-17 production in cultured splenocytes, favoring an IL-10 phenotype. In contrast, IL-10 production by T cells was attenuated by activating TR-β signaling with sobetirome. Finally, the manipulation of TR-β signaling altered the severity of autoimmune disease: blocking TR-β reduced passive EAE and enhancing TR-β increased active EAE. These effects were accompanied by corresponding changes in the IL-10/IL-17 balance in encephalitogenic CD4+ T cells. In summary, our results demonstrate that TR-β signaling controls pathogenic Th cell function and autoimmunity.