An ITK - SLP-76 Y173 Axis Regulates TCR Signal Persistence and Thymic Development

SLP-76 Y173 is required in mouse thymocytes for persistent TCR signaling, including sustained PLC-gamma1, ERK, and p38 phosphorylation, and for normal thymic cellularity.

• Why it matters: ITK phosphorylates multiple TCR substrates, but the in vivo role of its SLP-76 Y173 site in thymocyte development and signal persistence was unclear.
• What they did: In mice, SLP-76 Y173 was mutated to phenylalanine (SLP-76 Y173F), and thymocytes were assessed for TCR/CD28-induced I-kappaB degradation, persistent phosphorylation, and calcium-flux persistence with or without ITK inhibition.
• The result: SLP-76 Y173F thymocytes showed reduced thymic cellularity, altered CD4/CD8 ratios and CD5 expression, decreased persistence of TCR-induced calcium flux, reduced ERK/p38 phosphorylation, and decreased CD4- iNKT1 production with increased innate-like CD4+ and CD8+ SP thymocytes.