Autoimmune diseases arise from the failure of self-tolerance. The recognition of self-antigen peptide–MHC (pMHC) complexes by the T-cell receptor (TCR) is the fundamental event triggering autoimmune pathogenesis. While traditional immunosuppressants provide broad systemic effects, they often compromise global immunity. Emerging molecular strategies aim to selectively disrupt the trimolecular complex—comprising the TCR, the antigenic peptide, and the MHC molecule—to induce antigen-specific tolerance. This review highlights the pMHC–TCR interaction as the primary molecular checkpoint for antigen-specific intervention. We discuss the structural basis of these interactions and their potential to redefine the therapeutic landscape for autoimmune diseases (ADs). We examine the molecular drivers of tolerance breakdown—including genetic susceptibility, molecular mimicry, post-translational modifications (PTMs), and ectopic MHC II expression—that shape the autoreactive T-cell landscape. This review examines current advancements in biological and pharmacological interventions, such as pMHC-decorated nanoparticles and soluble pMHC, to reprogram pathogenic T-cell response. We also explored CAR-T therapy strategies for autoimmune diseases, such as CAR-Treg, designed to precisely modulate pMHC-TCR signaling. Collectively, these precision interventions in immunological synapse assembly during autoimmune response are considered the basis for safer, antigen-specific immunotherapy capable of restoring self-tolerance without global immunosuppression.

Study of CD4⁺ T cell response and T cell receptor (TCR) specificity is crucial for understanding etiology of immune-mediated diseases and developing targeted therapies. However, solubility, accessibility, and stability of synthetic antigenic peptides used in T cell assays may be a critical point in such studies. Here we present a T cell activation reporter system using recombinant proteins containing antigenic epitopes fused with bacterial thioredoxin (trx-peptides) and obtained by bacterial expression. We report that co-incubation of CD4⁺ HA1.7 TCR⁺ reporter Jurkat 76 TRP cells with CD80⁺ HLA-DRB1*01:01⁺ HeLa cells or CD4⁺ Ob.1A12 TCR⁺ Jurkat 76 TRP with CD80⁺ HLA-DRB1*15:01⁺ HeLa cells resulted in activation of reporter Jurkat 76 TPR after addition of recombinant trx-peptide fusion proteins, containing TCR-specific epitopes. Trx-peptides were comparable with corresponding synthetic peptides in their capacity to activate Jurkat 76 TPR. These data demonstrate that thioredoxin as a carrier protein (trx) for antigenic peptides exhibits minimal interference with recognition of MHC-specific peptides by TCRs and consequent T cell activation. Our findings highlight potential feasibility of trx-peptides as a reagent for assessing the immunogenicity of antigenic fragments.

Study of CD4+ T-cell response and T-cell receptor (TCR) specificity is crucial for understanding etiology of immune-mediated diseases and developing targeted therapies. However, solubility, accessibility, and stability of synthetic antigenic peptides used in T-cell assays may be a critical point in such studies. Here we present a T-cell activation reporter system using recombinant proteins containing antigenic epitopes fused with bacterial thioredoxin (trx-peptides) and obtained by bacterial expression. We report that co-incubation of CD4+ HA1.7 TCR+ reporter Jurkat 76 TRP-cells with CD80+ HLA-DRB1*01:01+ HeLa-cells or CD4+ Ob.1A12 TCR+ Jurkat 76 TRP with CD80+ HLA-DRB1*15:01+ HeLa-cells resulted in activation of reporter Jurkat 76 TPR after addition of recombinant trx-peptide fusion proteins, containing TCR-specific epitopes. Trx-peptides were comparable with corresponding synthetic peptides in their capacity to activate Jurkat 76 TPR. These data demonstrate that thioredoxin as a carrier protein (trx) for antigenic peptides exhibits minimal interference with recognition of MHC-specific peptides by TCRs and consequent T-cell activation. Our findings highlight potential feasibility of trx-peptides as a reagent for assessing the immunogenicity of antigenic fragments.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a remarkably broad and heterogeneous autoantigen repertoire. While epitope spreading, aberrant B-cell activation, and molecular mimicry act in concert with defective apoptotic clearance and sustained type I interferon signaling to drive systemic autoreactivity, many clinical manifestations of the disease are highly localized. The involvement of neuropsychiatric, renal, cutaneous, pulmonary, vascular, and hepatic systems appears to be shaped by tissue-specific autoantigen exposure and local microenvironments, where shared immunopathogenic pathways give rise to organ-associated autoantigenic landscapes. This review develops the concept of organ-associated autoantigenic landscapes, defined here as context-dependent configurations in which autoantibody–autoantigen interactions intersect with regional microenvironments and may contribute to inflammatory cascades, complement activation, and cellular damage. Importantly, organ association does not imply strict organ specificity, as the same circulating autoantibody may acquire distinct clinical relevance across tissues depending on antigen accessibility and local effector conditions. By illustrating how specific autoantibody–autoantigen axes may translate systemic autoimmunity into restricted clinical patterns, this framework provides a unifying model for disease heterogeneity and supports the development of precision, antigen-targeted therapeutic strategies.