Class switch recombination (CSR) enables B cells to diversify antibody effector functions while preserving antigen specificity. This process involves activation-induced cytidine deaminase (AID)-mediated DNA lesions within transcribed donor and acceptor switch (S) regions of the Igh locus, followed by double-strand break repair through end-joining pathways. Recent advances have revealed that CSR is tightly regulated by transcriptional activation, chromatin topology, and dynamic loop extrusion, which together orchestrate the synapsis of distant S regions. Moreover, emerging evidence highlights the roles of transcriptional R-loops, G-quadruplex structures, and enhancer-driven chromatin remodeling in recruiting AID to S regions. In this article, we synthesize our current understanding of the mechanisms that control CSR, emphasizing how genome architecture and transcriptional dynamics collaborate with DNA repair pathways to maintain a balance between antibody diversity and genomic stability.
Peripheral sensory neurons, long appreciated for their role in detecting environmental stimuli, also play an active role in local and systemic immune responses. In response to tissue damage, the coordinated activation of peripheral sensory neurons and immune cells facilitates tissue repair. When dysregulated, however, these neuroimmune interactions can become maladaptive and contribute to chronic disorders such as chronic pain or headache. Recent single-cell transcriptomic studies have uncovered multiple distinct sensory neuron subtypes, each with unique molecular profiles, anatomical niches, and immune functions. In this review, we examine how distinct sensory neuron subtypes coordinate immune responses in barrier and internal tissues, forming cell type- and context-specific neuroimmune circuits. We also discuss how disruption of these circuits contributes to neuroinflammatory diseases such as atopic dermatitis and neuropathic pain. Clarifying these subtype-specific neuroimmune mechanisms offers a path toward more precise and effective therapies that target maladaptive neuroimmune circuitry in multiple disorders.
T cells are key mediators of adaptive immunity, yet their highly dynamic response states and immense T cell receptor (TCR) diversity pose challenges in deciphering their functional roles in human diseases. Recent advances in single-cell genomics and TCR sequencing provide unprecedented opportunities to resolve T cell heterogeneity, decode clonal response dynamics, and facilitate high-throughput antigen specificity mapping. In this review, we summarize major technological innovations that have transformed T cell research, from experimental tools for antigen-specific T cell profiling to machine learning frameworks for predicting interactions between the TCR and peptide-MHC (pMHC) and structural modeling powered by deep learning. We discuss current bottlenecks, including data limitations and model generalizability, and explore emerging strategies to guide the next generation of T cell discoveries. We argue that artificial intelligence and single-cell genomics will collectively pave the way for dissecting T cell heterogeneity, mapping TCR sequence to pMHC specificity, and interpreting these features in the context of clinical outcomes.
Recent advancements in single-cell omic technology and lineage-tracing approaches have established that functional and dysfunctional activities of the immune system are critically influenced by context-specific microenvironmental factors. Among stromal cells, fibroblasts are emerging as far more plastic and heterogeneous than previously appreciated, and an abundance of profound and unique connections with the functioning of distinct branches of the immune system and with the regulation of inflammatory processes in tissue homeostasis and pathological conditions have been revealed. In this article, we review the state-of-the-art in the biology of inflammatory fibroblasts, with a particular emphasis on their involvement in regulating, and in turn their regulation by, cells of the innate and adaptive immune systems in chronic nonmalignant diseases. We cover their ontogeny and distribution across tissues and their shared and unique transcriptional, biochemical, and immunological characteristics within distinct chronic inflammatory diseases, infections, and autoimmune conditions.
Emerging evidence underscores a key role for the tumor microenvironment in supporting or suppressing cancer immunity. Of note, pro- and antitumor immune activity is controlled by not only the types of immune cells present but also their spatial arrangement within a tumor. This evidence is supported by the observation that the organization of immune cells in specialized immune niches is more predictive for clinical outcome and immunotherapy response than is the mere presence of tumor immune infiltrates. In this review, we explore how spatial compartmentalization modulates immune function through concerted cellular interactions, localized signaling cascades, and the generation of protective environments. We integrate current knowledge on both established and emerging immune niches with variable complexity—shaped by cell diversity, cell density, and structural organization—and their functional impact on cancer immunity. Finally, we discuss the compelling therapeutic opportunities offered by the induction or modulation of these niches in tumors.
