Trends in Immunology最新文献

The maintenance of serum antibodies requires the persistence of plasma cells within the bone marrow (BM). However, little is understood about why relatively few BM plasma cells live for extended periods. We consider two opposing viewpoints. We first consider the notion that sustained antibody titers requires localization of plasma cells to specialized BM niches where they access cell extrinsic survival factors, including extracellular ATP (eATP). We then consider the alternative possibility that plasma cell survival requires optimized cell intrinsic control of antibody synthesis supported by eATP stimulation of purinergic receptors. Based on the latter view we propose that many BM plasma cells fail to achieve maximal longevity due to suboptimal protein homeostasis rather than compromised access to cell extrinsic survival cues.

Interleukin-27 (IL-27), a member of the IL-12 cytokine family, was long viewed primarily as a regulator of CD4⁺ T cell immunity. Subsequent studies revealed that IL-27 also directly modulates CD8⁺ T cells, displaying both stimulatory and inhibitory potential. Recent work extends this earlier literature, showing that IL-27 in infection and cancer can promote effector differentiation, sustain survival, and reverse dysfunction, often without the systemic toxicity associated with related cytokines. This review outlines the molecular features, signaling mechanisms, and cellular sources of IL-27, integrating emerging evidence from viral, tumor, and autoimmune settings. We propose that IL-27 operates not as an inherently pro- or anti-inflammatory cytokine but as a context-dependent tuner of CD8⁺ T cell cytotoxic immunity, offering new opportunities for therapeutic exploitation.

IL-22, produced by various cell types including T helper (Th) 17 cells and group 3 innate lymphoid cells (ILC3s), plays a pivotal role in gut homeostasis by acting on non-hematopoietic cells. It promotes epithelial barrier integrity, tissue repair, and antimicrobial defense. Beyond its established function in mucosal immunity, emerging evidence reveals IL-22's involvement in regulating intestinal metabolism and protecting against systemic metabolic dysregulation. This review highlights recent advances in preclinical mouse models and human clinical data in IL-22 biology, focusing on its dual role in immune defense and metabolic control. Given the strong link between inflammatory bowel disease (IBD) and metabolic disorders, we further discuss IL-22's therapeutic potential in mitigating both intestinal inflammation and related metabolic complications.

Recent research has shown that sequential colonization of the skin by various subsets of immune cells, particularly T cells, during perinatal stages forms layered surveillance networks crucial for maintaining skin tissue integrity and function. Here, we review our current understanding of key epigenetic and molecular mechanisms, along with maternal/external environmental factors, that regulate the sequential colonization of skin by different T cell subsets and their roles in establishing and maintaining skin tissue homeostasis. We propose that establishment of a skin-resident T cell system is developmentally programmed in coordination with maturation of skin structural barriers to adapt to environmental changes during perinatal stages, while dysregulation during this critical 'window of opportunity' could have lifelong impacts on the health of both the skin and body.

The NLRP3 inflammasome plays a central role in host defense against microbial infections but also contributes to inflammatory diseases. Functioning of NLRP3 strictly relies on two signals: a 'priming signal' that licenses NLRP3 activity and an 'activation signal' that triggers inflammasome assembly and downstream caspase-1 activation. The priming signal involves transcriptional upregulation of NLRP3 and diverse post-translational modifications that regulate its stability, subcellular localization, and protein-protein interactions. This multilayered regulation prevents untimely inflammasome activation while enabling its rapid assembly when both priming and activation signals are present. Here, we focus on the complexity of the priming signal and critically analyze and discuss how diverse post-translational modifications cooperate to prime NLRP3, controlling its activity in health and disease.

Germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) originates from the malignant transformation of germinal center B cells. This process is driven by transcriptional and epigenetic dysregulations, frequently caused by recurrent mutations and chromosomal translocations. These changes lead to a differentiation arrest associated with unchecked proliferation and survival. This review highlights key transcriptional and epigenetic dependencies that sustain the GCB-DLBCL phenotype and identifies therapeutic vulnerabilities. Epigenetic targeting of these vulnerabilities unlocks tumor cells from their differentiation arrest, enabling further yet incomplete differentiation toward an antiproliferative, proapoptotic plasma cell-like or memory B cell-like state. We define this transition as an epigenetically programmed identity crisis, a promising therapeutic strategy to target GCB-DLBCL and potentially other malignancies.

Despite an effective combination of antiretroviral therapy, HIV persists as a lifelong infection and global health threat. The human host equips restriction factors and interferon (IFN)-stimulated genes that target every step of the viral life cycle. However, HIV-1 has evolved a coordinated immune evasion strategy using a limited set of accessory proteins with distinct antagonistic functions. This functional division of labor allows HIV-1 to disable key immune pathways and ensure persistence. Here, we explore the molecular interplay between host defenses and HIV-1, organizing antiviral factors by viral life cycle stage. We further reframe viral immune evasion as a strategic division of labor among accessory proteins each adapted to target specific host defenses, offering insights for next-generation therapies.

Immune activity at the cerebrospinal fluid (CSF)-dura-brain interface regulates key functions of brain physiology. In two back-to-back papers, Mamuladze et al. and Kothari et al. show that dural mast cells (MCs) are strategically positioned to coordinate this regulation, controlling CSF flow dynamics and immune cell trafficking in allergy, meningitis, and stroke.

Autoimmune diseases arise from genetic and environmental factors that disrupt immune tolerance. Recent studies highlight the role of myeloid cell immunometabolism, particularly mitochondrial dysfunction, in driving autoimmunity. Mitochondria regulate energy homeostasis and cell fate; their impairment leads to defective immune cell differentiation, abnormal effector activity, and chronic inflammation. We propose that chronic metabolic stress reprograms myeloid cells, fueling a vicious cycle of cell death and immune activation. Over time, this may induce several states of maladaptation in myeloid cells. Viewing autoimmune disease through a metabolic lens offers new insight into disease mechanisms and highlights potential therapeutic opportunities targeting mitochondrial function to restore immune balance.

The complement genes harbour genetic variants that affect numerous diseases; however, these genes are notoriously repeat-heavy, and these repeat regions are largely unexplored for disease-relevant genetic variation. Elucidating these 'dark' regions is now possible using long-read sequencing (LRS), enabling identification of novel disease-relevant genetic variants.