Mapping the Altered Landscape of TCR Repertoire in Autoimmune Diseases

Autoimmune diseases arise from the breakdown of immune tolerance through complex interactions between genetic predisposition, environmental exposures, and adaptive immune responses. High-throughput T-cell receptor (TCR) repertoire sequencing has transformed our ability to characterize these responses, providing unprecedented insights into clonal dynamics, antigen-driven selection, and immune history. In this review, we summarize the major alterations of TCR repertoires reported across autoimmune diseases, including changes in diversity, clonal expansion, repertoire architecture, and tissue distribution. We discuss the principal biological and technical challenges that currently limit repertoire interpretation, with particular emphasis on the concept that bulk repertoires represent composite mixtures of biologically distinct T-cell populations. Finally, we highlight emerging approaches integrating single-cell profiling, computational modeling, and antigen-specificity inference that are reshaping the field. We propose that TCR repertoires should be viewed as dynamic molecular footprints of autoimmune disease, providing a systems-level framework to improve mechanistic understanding, biomarker discovery, and the development of precision immunotherapies.