Trends in Immunology最新文献

Interactions between autoimmune disorders and lymphoid malignancies have long been recognized; for instance, with prominent autoimmune manifestations in B- and T-cell lymphomas and an increased risk of lymphoma development in individuals with autoimmune diseases. More recently, several lines of evidence have shown that these two disease types have shared origins, defined by common genetic lesions and pathogenic cell states. Recent work suggests that the safeguards that protect normal lymphocyte development and adaptive immunity against the development of autoimmune diseases and lymphoid malignancies are based on similar sensing mechanisms of pathological lymphocytes. Here, we propose that mechanisms of negative selection that are designed to eliminate autoreactive lymphocytes also operate in suppressing the development of lymphoid malignancies.

Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment (TME), but their heterogeneity, driven by tumor-derived cues, poses challenges for therapeutic targeting and underscores the need for precise macrophage reprogramming strategies. Through a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen, Marelli et al. identified chemosensors as lipid-sensing regulators of macrophage activity, revealing new therapeutic avenues.

Humanized mouse models with transgenic expression of human myelopoiesis-supporting growth factors have enhanced human myeloid cell engraftment and improved the study of human innate immune responses. Here, we discuss the remaining challenges associated with studying innate immunity in humanized NSG-SGM3 and MISTRG mice, as well as potential advances to overcome them.

An allelic variant of the autophagy gene ATG16L1 (T300A) is a genetic risk factor for Crohn's disease. However, over 50% of the global population carries at least one copy. Yao et al. have demonstrated a heterozygote advantage, where the pathogen-protective effect of one allele may outweigh the disease risk in homozygotes.

Chronic inflammation drives diseases like osteoarthritis and MASH, yet its molecular distinction from acute inflammation remains unclear. In a recent Nature study, Wang et al. revealed that chronic stress triggers WSTF degradation via nuclear autophagy, amplifying NF-κB responses. Blocking this pathway attenuates chronic inflammation while sparing acute immunity.

The immunological tolerance protecting the fetus from maternal rejection during pregnancy involves nonclassical human leukocyte antigen (HLA) class I molecules (HLA-G, HLA-E, HLA-F) interacting with maternal immune-inhibitory receptors. Cancers similarly exploit these molecules to evade immune detection and promote tumor progression. Pseudogenes within the major histocompatibility complex may modulate these pathways via noncoding RNA, gene conversion, or protein interactions, although their precise roles remain unclear. Furthermore, fetal-maternal microchimerism potentially reinforces maternal tolerance but could also influence susceptibility to autoimmune disorders or cancer. This review critically evaluates current experimental evidence, identifies knowledge gaps, and proposes therapeutic approaches targeting these pathways in oncology without compromising maternal-fetal tolerance.

FOXP3⁺ regulatory T cells (Tregs) are essential for maintaining immune tolerance, and their dysfunction is a hallmark of autoimmune diseases. Recent studies have identified key transcriptional, metabolic, and environmental drivers of Treg instability and loss of function. Understanding these mechanisms opens new avenues for therapeutic interventions aimed at restoring immune homeostasis in autoimmunity.

The border tissues of the brain harbor specialized immune cells known as border-associated macrophages (BAMs), which have vital roles at these interfaces. However, factors governing their development and maintenance remain elusive. In a recent study, Van Hove et al. elegantly demonstrated that interleukin (IL)-34 is critical for sustaining BAMs and enabling their regulation of vascular function.

Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease caused by motor neuron loss. In a recent Phase 2b trial, Bensimon and colleagues report that the addition of low-dose interleukin 2 (LD-IL-2) immunotherapy to standard of care (SOC) shows promise in enhancing immune tolerance and improving survival in individuals with slower disease progression.

CD4 T cell tolerance is essential for immune homeostasis but its mechanisms remain unclear. Although regulatory T cells (Tregs) mediate T cell-extrinsic tolerance, this review emphasizes the CD4 T cell-intrinsic pathways - anergy and exhaustion - that are triggered by suboptimal or persistent antigen stimulation. These states share transcriptional and epigenomic features across contexts such as cancer, pregnancy, and transplantation. Instead of being distinct, they form a spectrum of tolerance with potential for therapeutic targeting. CD154 has re-emerged as a promising target, although memory T cell tolerization remains challenging. A deeper understanding of what sustains or reverses CD4 T cell tolerance is key to designing treatments that induce/maintain tolerance in autoimmunity and transplantation, or restore functionality in cancer and chronic infection.