LCK'ed in: Inborn errors of immunity in LCK reveal how TCR signaling is calibrated

TCR signaling must be precisely calibrated to guide thymic selection, lineage commitment, and immune homeostasis. LCK, the dominant proximal Src-family kinase in T cells, functions as a volume dial governing initial TCR signal amplitude. Human inborn errors of immunity affecting LCK (LCK-IEI) demonstrate that graded reductions in LCK translate into distinct developmental and clinical outcomes. Null or near-null variants silence αβ thymocyte output, resulting in profound immunodeficiency, whereas hypomorphs permit limited thymopoiesis but selectively impair regulatory T cell development, skew TCR repertoires, and drive autoimmunity. Notably, γδ T cells are preserved, underscoring lineage-specific signaling thresholds. Signaling defects downstream of LCK produce overlapping phenotypes, confirming T cell fate reflects signal strength, not molecular identity. Here, we synthesize insights from human LCK-IEI and emerging spatial views of thymic microenvironments to define how quantitative and contextual regulation of TCR signaling shapes selection, tolerance, and immune balance. We highlight unresolved questions and experimental strategies aimed at restoring immune sufficiency while avoiding immune dysregulation.