Antiretroviral therapy (ART) has shifted HIV-1 infection into a manageable chronic condition. However, immune reconstitution is occasionally complicated by the de novo emergence of autoimmune diseases (AiDs), presenting a profound immunological paradox. This review evaluates the molecular, phase-specific pathogenetic sequence driving ART-induced autoimmunity at the intersection of cytokine networks, host genetics, and nuclear senescence. A systematic literature search (1985-2026) was conducted across PubMed, Embase, and Scopus using high-density Boolean strings targeting HIV, AiDs, immune reconstitution inflammatory syndrome, cytokines, and telomeric metrics. Results indicate that immune repopulation occurs in distinct phases matching memory and naive T-cell waves. Host immunogenetics heavily regulate susceptibility; mathematical derivation yields a Relative Risk (RR) ratio of 1.12 for individuals lacking the protective HLA-DRB1*13 allele. Chronic retroviral stress and high reactive oxygen species accelerate telomeric erosion. Critically shortened telomeres are associated with a DNA damage response, which may promote an immune cell transition into a Senescence-Associated Secretory Phenotype (SASP) marked by elevated Interleukin-6 (IL-6) secretion. Elevated IL-6 signaling is linked to altered peripheral tolerance, potentially shifting the Th17/Treg axis toward pathogenic Th17 cell differentiation. Post-ART autoimmunity is associated with accelerated immunosenescence, Th17/Treg imbalances, and hypothesized post-transcriptional controls governed by the Arid5a/Regnase-1 balance over IL-6 transcripts.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, yet classical suppressive mechanisms alone do not fully explain how tolerance is propagated across tissues and sustained over time. Extracellular vesicles (EVs), particularly exosome-enriched small EVs, have emerged as an important additional layer of Treg-associated communication by enabling the selective transfer of proteins, lipids and regulatory RNAs between cells. In this review, we examine the reciprocal EV-Treg axis, highlighting how Treg-derived EVs extend suppressive function beyond direct cell contact by modulating dendritic cells, restraining effector T-cell responses, promoting regulatory macrophage polarization and supporting tissue repair. We further discuss how EVs released by immune, epithelial, stromal, microbial and tumor-associated cells shape Treg differentiation, stability and functional specialization in diverse physiological and pathological settings. Across autoimmunity, transplantation, barrier inflammation, infection and cancer, this bidirectional crosstalk emerges as a context-dependent regulator of immune tolerance that may either preserve tissue homeostasis or promote pathological immune suppression. We finally consider the therapeutic potential of targeting or engineering EV-Treg interactions as a cell-free strategy for precision immunomodulation.

Persistent infection with high-risk human papillomavirus (HPV) is the essential precursor to cervical carcinogenesis and remains a major global health challenge despite advances in vaccination and screening. While most cervical HPV infections are spontaneously cleared, a subset persists and progresses to cervical intraepithelial neoplasia (CIN) and ultimately invasive cervical cancer. Emerging evidence identifies nuclear factor kappa B (NF-κB) as a central regulator linking antiviral immunity, chronic inflammation, epithelial survival, and disease progression. In this hybrid review, we systematically synthesize clinical evidence regarding NF-κB activation in persistent cervical high-risk HPV infection and integrate mechanistic insights from molecular studies to develop a translational framework for therapeutic intervention. Current data suggest that HPV oncoproteins E6 and E7 selectively reprogram NF-κB signaling, attenuating antiviral interferon responses while maintaining inflammatory pathways that favor viral persistence and immune dysregulation. A stage-dependent model emerges in which early suppression of antiviral signaling is followed by chronic low-grade NF-κB activation, promoting epithelial survival, microenvironmental remodeling, and progression toward high-grade CIN. We further discuss pathway-specific therapeutic opportunities, including selective NF-κB modulation and integration with therapeutic E6/E7 vaccination. Collectively, NF-κB represents a promising biomarker and therapeutic target for host-directed strategies aimed at viral clearance and prevention of cervical cancer progression.

Aging-associated immunosenescence disrupts various immune pathways-signaling, cellular, metabolic, epigenetic, and inflammatory mechanisms-leading to impaired bidirectional interactions between the immune system and organs. This dysfunction exacerbates geriatric conditions, including neurodegenerative disorders, chronic inflammation, and metabolic syndromes. This review introduces the concept of the immune-organ axis, an underexplored framework connecting immune dysregulation to organ-specific dysfunction. Nutritional interventions, including bioactive compounds, essential nutrients, functional foods, and phytochemicals, are highlighted for their ability to modulate these pathways by inducing autophagy, resolving inflammation, and promoting cellular repair. Furthermore, stabilization and delivery systems are proposed as technological solutions to enhance the efficacy of these interventions. This review emphasizes the need for integrative approaches to mitigate immune dysfunction and improve health outcomes in aging populations, while outlining future research directions to advance this field.

Demyelination of the Central Nervous System (CNS) is a pathological process that causes the destruction of the myelin sheath, the insulating cover that protects the nerve fibres. This serves as one of the major attributes of numerous neurological disorders, such as Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD), Acute Disseminated Encephalomyelitis (ADEM), Myelin Oligodendrocyte Glycoprotein-related antibody disease (MOGAD), etc. It is usually initiated as an immune-mediated injury to myelin, followed by dysregulation of the immune system and ultimately failure of effective remyelination. Although oligodendrocytes in the CNS have some capacity for regeneration, the surrounding microenvironment severely inhibits their function, which results in a reduced regenerative outcome. Previously referred to as suppressor T cells, regulatory T cells (Tregs) are a subset of T cells that were traditionally thought to have an immunosuppressive function. However, it has just recently been shown that they directly contribute to regeneration and repair. The goal of this review is to demonstrate how Tregs can promote regeneration by balancing a variety of underlying molecular and cellular processes. Recent research shows that Tregs affect oligodendrocyte lineage progression, microglial and astrocytic responses, and the milieu around the demyelination site in order to perform remyelination. These effects are age-dependent and occur both temporally and geographically. In order to offer an evolutionary perspective on the conserved immune-mediated regenerative pathways that may be diminished in mammals and can be further investigated for therapeutic purposes, this review also aims to draw comparisons between the mechanisms used by regeneration-competent and non-competent species.

Regulatory T cells (Tregs) are essential mediators of immune tolerance that maintain tissue homeostasis by restraining excessive immune activation. In cancer, these regulatory mechanisms are reinforced within malignant tissues and contribute to suppression of endogenous anti-tumor immunity. Tumor-infiltrating Tregs (TI-Tregs) represent a specialized activation state shaped by chronic antigen exposure, inflammatory cytokines, stromal cues, and metabolic stress imposed by the tumor microenvironment (TME). Rather than functioning as a static suppressive lineage, intratumoral Tregs integrate receptor-mediated signaling, FOXP3-centered transcriptional stabilization, and metabolic licensing, and spatial niche formation to maintain suppressive fitness under hypoxic and nutrient-restricted conditions. This review synthesizes current understanding of the molecular and metabolic programs that stabilize tumor-associated Tregs and organizes them into an integrated framework linking antigen-driven activation, regulatory identity, metabolic adaptation, tissue-contextual reprogramming, and therapeutic resistance. We further discuss emerging therapeutic strategies aimed at selectively modulating tumor-associated regulatory states while preserving systemic immune tolerance, with explicit attention to preclinical versus clinical evidence, tumor-type specificity, and toxicity risks.

Leptin, a multifunctional hormone primarily secreted by adipose tissue, plays a crucial role in regulating body weight, appetite, energy expenditure, and metabolic processes. Beyond regulating metabolic pathways, leptin demonstrates notable immunoregulatory capabilities. It modulates a wide range of biological functions, including glycemic control, hematopoietic processes, and bone metabolism. The discovery of leptin has significantly advanced our understanding of the crosstalk between metabolic homeostasis and immune system functionality. Recent research highlights its critical role in immune responses, particularly in modulating T lymphocytes. This hormone transmits nutritional signals to the immune system, promoting pro-inflammatory Th1 and Th17 responses while inhibiting anti-inflammatory Treg cell proliferation. Consequently, it is a pivotal regulator integrating metabolic signals to control the balance between inflammation and immune tolerance. In this review, we will synthesize the latest advancements in leptin research, leptin receptor signaling, the hormone's impact on T cells and immune responses, as well as its potential pathogenic roles in autoimmune diseases, including Systemic Lupus Erythematosus (SLE), psoriasis, vitiligo, and other autoimmune disorders. Our objective is to provide a comprehensive analysis of leptin's properties and its unique roles in autoimmune conditions, with the aim of providing new insights into effective and holistic therapeutic strategies.

Metabolic reprogramming within the tumor microenvironment (TME) is a pivotal driver of CD8[+] T cell dysfunction in cancer. Tumor cells outcompete T cells for essential nutrients, including glucose and amino acids, while accumulating immunosuppressive metabolites such as lactate and 2-hydroxyglutarate. Beyond direct functional impairment, emerging research reveals that these metabolic alterations orchestrate CD8[+] T cell transcriptional programs by remodeling their epigenome-via histone modifications, DNA methylation, and non-coding RNA networks-thereby dictating their differentiation, cytotoxic potential, and memory formation. A deeper understanding of how TME-derived metabolic signals shape the epigenetic landscape of CD8[+] T cells is crucial for improving current cancer immunotherapeutic strategies. This review systematically delineates how key TME metabolic features, including nutrient deprivation and oncometabolite accumulation, regulate CD8[+] T cell fate through epigenetic pathways. Furthermore, we discuss promising therapeutic strategies that target the metabolism-epigenetics axis to reinvigorate CD8[+] T cell anti-tumor immunity, offering novel perspectives for enhancing adoptive cell therapy and immune checkpoint blockade.

The gut represents a melting pot of distinct classes of antigens derived from self antigens, dietary components, and the commensal microbiota. To maintain tolerance to innocuous antigens while preserving the capacity to respond to potentially harmful microorganisms, the immune system has evolved tightly regulated mechanisms centered on the generation of Foxp3[+] regulatory T (Treg) cells at mucosal surfaces. Although early insights into intestinal Treg development were largely derived from studies using model dietary antigens or selected microbial species, a substantial gap remains in our understanding of the natural antigen landscape that elicits Treg responses in vivo. In this review, we discuss recent advances based on TCR classification approaches that define intestinal Treg T cell receptor (TCR) responses according to in vivo antigen reactivity, and we highlight key future directions for elucidating the functional roles of antigen-presenting cell subsets and their associated peptide landscapes in shaping intestinal Treg biology.

Using cytotoxic CD8[+] T cell-mediated cellular immunity has shown considerable efficacy in cancer treatment. However, the effectiveness of these cells against solid tumors is limited by the presence of an immunosuppressive tumor microenvironment (TME), which constitutes complex networks of regulatory pathways and resistance mechanisms. Given its critical role in TME deterioration through shedding of immunosuppressive molecules from tumor and immune cell surfaces, the upregulation of A Disintegrin and Metalloproteinase 10 (ADAM10) expression can reinforce CD8[+] T cells into a state of exhaustion. This paper highlights the influence of ADAM10 and its proteolytic products on the primary pathways of CD8[+] T cell exhaustion, including the expression of immune checkpoint molecules and modification across CD8[+] T cell transcriptional, metabolic, and nutritional states. We remain optimistic about the critical role of ADAM10 in cytokine-induced T cell exhaustion, recruitment of immunosuppressive cells into the TME, and CD8[+] T cell death/survival. Gaining significant insights into these processes may offer new strategies to advance CD8[+] T cell-mediated cancer therapy.

Granulomatous mastitis (GM) is an inflammatory breast disease. Pentraxin 3 (PTX3) is frequently dysregulated in inflammatory diseases. C. parakroppenstedtii. infection was applied to establish a rat GM model. Histological analysis showed that the progression of GM was accompanied with the damage of DECs. The serum and mRNA levels and protein expression of PTX3 was increased in GM rat models. PTX3 overexpression drove macrophage to M2 macrophage polarization, inhibiting inflammation response. PTX3 overexpression promoted clearance of apoptotic mammary duct epithelial cells (DECs) by M2 macrophages. However, PTX3 depletion in macrophage inhibited M2 macrophage polarization and impaired the efferocytotic ability, mediating inflammatory response and accumulation of apoptotic DECs. In summary, PTX3 exerts protective function in GM. PTX3-mediated M2 macrophage polarization promotes the clearance of apoptotic DECs. Therefore, targeting the communication between macrophages and DECs may be a promising strategy for GM.

Dysregulated B lymphocyte activation plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), making it a promising target for therapeutic intervention. Chimeric antigen receptor T cell (CAR-T) therapy, specifically targeting CD19-positive B cells, has shown potential in selectively eliminating aberrant B cells, offering a path toward sustained remission and even complete eradication of SLE. However, the broad immunosuppressive effects and cytotoxicity associated with CAR-T therapy pose significant challenges to its application in autoimmune disease treatment. Recent advances in extracellular vesicle biology, particularly exosomes, have highlighted their potential as a cell-free therapeutic platform due to their superior biocompatibility, plasticity, and ability to modulate immune responses. CAR-T-derived or engineered exosomes represent a potential cell-free alternative to reduce cellular dose and toxicity while preserving efficacy in SLE. This review provides a comprehensive analysis of the current landscape of CAR-T cell therapy in autoimmune diseases, with a focus on its safety, effectiveness, and potential in treating SLE. Furthermore, it explores the emerging role of exosomes as a promising adjunct to traditional CAR-T therapy, offering novel perspectives and therapeutic strategies for SLE management.

Psoriasis is a chronic, immune-mediated inflammatory disorder with systemic implications beyond its cutaneous manifestations. Its pathogenesis involves a complex interplay between genetic predisposition, environmental triggers, and immune dysregulation. The sustained crosstalk between dendritic cells (DCs) and T cells, which orchestrates the initiation and perpetuation of psoriatic inflammation. Plasmacytoid DCs, activated by nucleic acid-LL37 complexes, produce interferon-α that promotes myeloid DC maturation. These DCs secrete IL-12, IL-23, and TNF-α, driving differentiation of naïve T cells into Th1, Th17, and Th22 subsets. Effector T cells subsequently release cytokines such as IFN-γ, IL-17, and IL-22, which promote keratinocyte hyperproliferation, impaired differentiation, neutrophil recruitment, and angiogenesis. This DC-T cell axis forms a self-amplifying inflammatory loop that underpins disease chronicity. Conventional systemic agents, including methotrexate, cyclosporine, and retinoids, have demonstrated efficacy but are limited by nonspecific immunosuppression and significant toxicities. Advances in immunology have identified the IL-23/Th17 pathway as a pivotal therapeutic target, enabling the development of biologics and small-molecule inhibitors. Monoclonal antibodies targeting TNF-α, IL-12/23, IL-17, and IL-23 have revolutionized management, achieving high rates of sustained clearance with improved safety profiles. Additional strategies, such as PDE4 and JAK/STAT inhibitors, offer oral alternatives with targeted immunomodulation. Novel approaches, including tolerogenic DC therapy and neuroimmune modulation, hold promise for refining treatment and addressing disease heterogeneity. Effective immunotherapeutic strategies must therefore balance skin clearance with reduction of systemic inflammation and long-term comorbidity risk. Integrating mechanistic insights into DC-T cell interactions with emerging therapies provides a framework for personalized, safer, and more durable disease control.

Head and neck cancers (HNCs) pose a significant global health challenge, with treatment complexities and profound impacts on patient quality of life. Tumor-infiltrating B cells (TIBs) within the tumor microenvironment (TME) are emerging as critical yet dual regulators of HNC immunity, exhibiting both pro- and anti-tumorigenic properties. This manuscript explores the prognostic and predictive roles of TIBs across diverse HNCs, including squamous cell carcinomas and lymphomas. TIBs enhance antitumor immunity through antibody production, antigen presentation, and the formation of tertiary lymphoid structures (TLSs), which correlate with improved survival and response to immune checkpoint inhibitors (ICIs). Conversely, regulatory B cells contribute to immunosuppression, promoting tumor progression. Notably, high TIB infiltration, particularly within TLSs, is associated with superior outcomes in ICI-treated patients, highlighting their potential as biomarkers and therapeutic targets. However, challenges such as data variability and limited study scales underscore the need for further investigation into TIB subpopulations and their molecular dynamics. Future research should prioritize understanding TIB interactions with other immune cells and developing novel immunotherapies, including genetic engineering and oncolytic viruses, to advance HNC treatment and optimize patient outcomes.