Signaling and Transcriptional Control of Thymocyte Differentiation

This review summarizes key topics discussed in the session "Biology within the Thymus" at the 54th Annual Meeting of the Japanese Society for Immunology, which highlighted recent advances in our understanding of T-cell development and fate determination. In particular, the session focused on transcriptional regulation of T-lineage commitment and the mechanisms by which T-cell receptor (SP) signaling governs thymocyte differentiation. Early T-lineage commitment is established through the integration of thymic microenvironmental cues and intrinsic transcription factors, including Bcl11b, PU.1, and Runx family proteins. Among these, Runx transcription factors play essential roles throughout thymocyte development, not primarily through changes in expression but through dynamic regulation of their molecular interactions and genomic occupancy. Following commitment, αβTCR-expressing CD4+CD8+ double-positive (DP) thymocytes undergo MHC-dependent selection and differentiate into CD4+ helper or CD8+ cytotoxic T cells. Although the core components of proximal TCR signaling are largely shared, accumulating observations suggest that qualitative and quantitative differences in signaling-shaped by signal strength, duration, and subcellular context-may contribute to lineage specification. In this regard, recent studies discussed in this session highlighted the role of co-receptor-free Lck as an active signaling pool capable of initiating TCR signaling independently of CD4 or CD8 association, thereby adding an additional layer of complexity to MHC-dependent thymic selection. In addition, post-translational modification of Runx proteins, particularly within the conserved WRPY motif, has emerged as a molecular link between proximal TCR signaling mediated by kinases such as Lck and lineage-specific transcriptional repression. Together with advances in thymic culture systems, genome editing, and proteomic approaches, these findings underscore the tight coupling between proximal TCR signaling-including both co-receptor-dependent and co-receptor-independent Lck activity-and transcriptional regulation, and highlight Runx transcription factors as key integrators that translate MHC-specific TCR signals into transcriptional programs determining thymocyte fate.