eIF3a is a N 6-methyladenosine (m6A) reader that regulates mRNA translation by recognizing m6A modifications of these mRNAs. It has been suggested that eIF3a may play an important role in regulating translation initiation via m6A during infection when canonical cap-dependent initiation is inhibited. However, the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo. In this study, we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage, which contributed to severe sepsis induced by Lipopolysaccharide (LPS). Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis. We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m6A modification of mRNAs. These findings unveil a novel mechanism underlying sepsis, implicating the pivotal role of B cells in this complex disease process regulated by eIF3a. Furthermore, eIF3a may be used to develop a potential strategy for treating sepsis.
© 2025 The Authors.

MRL/lpr mice develop systemic lupus erythematosus-like autoimmunity due to defective FAS-mediated apoptosis. We generated Fas lpr mice deficient in EAF2, a transcription elongation-associated factor known to promote apoptosis in germinal center (GC) B cells and crucial for preventing autoimmunity. Contrary to expectations, EAF2 deficiency significantly reduced lymphadenopathy and splenomegaly, extended lifespan, and alleviated nephritis by decreasing renal immune complex deposition. Additionally, EAF2 deficiency markedly reduced accumulation of activated B cells, GC B cells, plasma cells, and the abnormal B220+CD3+ T cells in Fas lpr mice. Further analysis revealed that Eaf2 -/- Fas lpr B cells showed hyperactivation upon various stimulations, followed by increased death. RNA sequencing of the B220+CD3+ cells revealed a downregulation in survival-promoting genes such as Bcl-2 and Akt and an upregulation of proapoptotic genes. We conclude that the combined deficiency in FAS- and EAF2-mediated apoptotic pathways leads to B cell hyperactivation and subsequent death, thereby ameliorating systemic autoimmunity in this model.
© 2024 The Author(s).

In B lymphocytes, class switch recombination (CSR) is an essential process that adapts immunoglobulin (Ig) subtypes to antigen response. Taking place within the Ig heavy chain (IgH) locus, CSR needs controlled transcription of targeted regions governed by the IgH 3' regulatory region (3'RR). This super-enhancer is composed of four core enhancers surrounded by inverted repeated sequences, forming a quasi-palindrome. In addition to transcription, nuclear organization appears to be an important level in CSR regulation. While it is now established that chromatin loop extrusion takes place within IgH locus to facilitate CSR by bringing the donor and acceptor switch regions closer together, the underlying mechanism that triggers CSR loop formation remains partially understood. Here, by combining DNA 3D fluorescence in situhybridization with various high-throughput approaches, we deciphered critical functions for the 3'RR core enhancer element in nuclear addressing, accessibility and chromatin looping of the IgH locus. We conclude that the 3'RR core enhancers are necessary and sufficient to pre-organize the position and conformation of IgH loci in resting B-cell nuclei to enable the deletional recombination events required for productive successful CSR in activated B-cell nuclei.
© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.

Tumor cell-originated events prevent efficient antitumor immune response and limit the application of anti-PD1 checkpoint immunotherapy. We show that syndecan-1 (SDC1) has a critical role in the regulation of T cell-mediated control of tumor growth. SDC1 inhibition increases the permeation of CD8+ T cells into tumors and triggers CD8+ T cell-mediated control of tumor growth, accompanied by increased proportions of progenitor-exhausted and effector-like CD8+ T cells. SDC1 deficiency alters multiple signaling events in tumor cells, including enhanced IFN-γ-STAT1 signaling, and augments antigen presentation and sensitivity to T cell-mediated cytotoxicity. Combinatory inhibition of SDC1 markedly potentiates the therapeutic effects of anti-PD1 in inhibiting tumor growth. Consistently, the findings are supported by the data from human tumors showing that SDC1 expression negatively correlates with T cell presence in tumor tissues and the response to immune checkpoint blockade therapy. Our findings suggest that SDC1 inhibits antitumor immunity, and that targeting SDC1 may promote anti-PD1 response for cancer treatment.

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness and fatigue. It is caused by pathological autoantibodies against components expressed at neuromuscular junctions, such as acetylcholine receptor (AChR). Interleukin-6 (IL-6) has been suggested to play a role in the pathogenesis of MG, and IL-6 receptor (IL-6R) antibody treatment may provide a novel therapeutic option. In this study, we investigated the effects of IL-6R antibody treatment in an experimental autoimmune MG (EAMG) mouse model. We demonstrated that IL-6R antibody treatment improved muscle weakness, reduced IgG deposition at neuromuscular junctions, and the levels of AChR autoantibodies in serum. In addition, follicular helper T cells and Th17, plasma cells in lymph nodes were lower in IL-6R antibody treated mice. Our findings suggest that IL-6R blockade may be a novel and effective therapeutic strategy for the treatment of MG.
Copyright © 2024 Miyake, Serizawa, Onishi, Katsura, Baba, Kurasawa, Tomizawa-Shinohara, Yorozu, Matsumoto and Noguchi-Sasaki.