Inflammatory and oxidative stress within the pancreatic islet microenvironment can alter insulin-derived peptides and generate neoepitopes that may reshape autoreactive T cell recognition in type 1 diabetes (T1D). One such modification, C19S, represents a cysteine-to-serine substitution at position 19 of the insulin B-chain and has recently been identified among human leukocyte antigen class II (HLA-II)-associated insulin neoepitopes recognized by autoreactive CD4+ T cells. Although the biological relevance of C19S has been determined, the molecular features that may distinguish C19S-specific T cell receptor (TCR) engagement from native insulin recognition remain incompletely defined. Here, we used comparative protein–protein docking, molecular dynamics (MD) simulations, interface-contact analysis, conformational landscape analysis, and binding-energy calculations to examine TCR engagement of human leukocyte antigen DQ8 (HLA-DQ8) presenting either native insulin peptide or the corresponding C19S insulin peptide. Initial modeling indicated that both peptide-HLA-DQ8 complexes were compatible with TCR-bound ternary complex formation. However, the C19S-containing complex was predicted to exhibit altered peptide-centered dynamics, changes in peptide backbone presentation, and reorganization of both TCR-peptide and TCR-HLA-DQ8 contacts. Comparative molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) analyses further suggested a distinct calculated energetic profile under the applied modeling conditions for the C19S-containing complex, with residue-level decomposition localizing energetic differences to selected interface hotspots. Together, these findings provide a molecular framework for generating hypotheses about how C19S may reshape the HLA-DQ8-presented insulin recognition surface, with implications for future experimental studies of autoreactive CD4+ T cell recognition and antigen-specific tolerogenic strategies in T1D.
Rahul Mittal, F. Alipour, Prem P. Chapagain et al.· International Journal of Mol...· 0 citations
Aging is increasingly recognized as a heterogeneous biological process rather than a uniform chronological phenomenon. Immunosenescence has emerged as a central hallmark of biological aging, profoundly shaping susceptibility to infection, malignancy, autoimmunity, and poor vaccine responses. This progressive decline encompasses both innate and adaptive immunity and is marked by impaired antigen presentation, thymic involution, reduced lymphopoiesis, repertoire contraction, and the establishment of chronic low-grade inflammation. Importantly, immunosenescence does not occur solely as a consequence of chronological time but is accelerated by chronic conditions such as human immunodeficiency virus (HIV) infection, autoimmune disease, metabolic syndrome, chronic kidney disease, and cancer therapy, underscoring the dissociation between chronological and biological immune age. At the molecular level, aged lymphocytes accumulate DNA damage, mitochondrial dysfunction, and metabolic stress that drive canonical senescence pathways. Classical markers, including p16 inhibitor of cyclin-dependent kinase 4a (p16INK4a), p21 cyclin-dependent kinase–interacting protein 1 (p21CIP1), gamma-H2A histone family member X (γH2AX), and senescence-associated β-galactosidase (SA-β-gal), are now complemented by novel signatures such as immune-specific DNA methylation clocks, histone modifications, noncoding RNA networks, telomeric repeat-containing RNAs, mitochondrial dysfunction metrics, and profiles of the senescence-associated secretory phenotype. These biomarkers provide quantitative measures of immune biological age that surpass chronological metrics in predicting health outcomes. This review synthesizes emerging molecular and epigenetic frameworks that redefine immunosenescence as a quantifiable and disease-modifiable dimension of biological aging rather than a passive consequence of chronological time. By integrating immune-specific epigenetic clocks, mitochondrial and telomeric stress signatures, and senescence-associated secretory phenotypes, we highlight actionable biomarkers that enable precise stratification of immune biological age. These insights provide a translational roadmap for targeting immune aging through senotherapeutics, metabolic and epigenetic interventions, and optimized vaccine strategies, advancing immunosenescence toward precision geromedicine. Future advances will arise from longitudinal studies employing single-cell multi-omics, repertoire sequencing, and artificial intelligence–driven modeling to refine predictive aging clocks. Translational strategies targeting immune aging, including senolytics, senomorphics, metabolic modulators, epigenetic reprogramming, and next-generation vaccine adjuvants, hold promise for restoring immune resilience. Integrating these insights into precision medicine frameworks may transform immunosenescence from an inevitable feature of aging into a modifiable determinant of healthspan.