Bulk T cell repertoire sequencing (TCR-Seq) is a powerful technology for understanding inflammation-mediated diseases.

Multiple alterations in the T cell repertoire were identified in many chronic inflammatory diseases such as inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis, suggesting that T cells might, directly or indirectly, be implicated in these pathologies. This has sparked a deep interest in characterizing disease-associated T cell clonotypes as well as in identifying and quantifying their contribution to the pathophysiology of different autoimmune and inflammation-mediated diseases. Bulk T cell repertoire sequencing (TCR-Seq) has emerged as a powerful method to profile the T cell repertoire of a sample in a high throughput fashion. Given the increasing utilization of TCR-Seq, we aimed here to provide a comprehensive, up-to-date review of the method, its extensions, and its ability to investigate chronic and autoimmune diseases. Specifically, we started by introducing the immunological basis of TCR repertoire generation and features, followed by discussing different experimental approach to perform TCR-Seq, then we describe different methods and frameworks for analyzing the generated datasets. Subsequently, different experimental techniques for investigating the antigenicity of T cell clonotypes are described. Lastly, we discuss recent studies that utilized TCR-Seq to understand different inflammation-mediated diseases, discuss fallbacks of the technology and potential future directions to overcome current limitations.