Year: 2026
Type: preprint
Abstract: The TCR-induced tyrosine kinase cascade results in ITK-mediated phosphorylation of at least two substrates: PLC-γ1 Y783, an essential mediator of TCR signaling, and SLP-76 Y173. We previously provided evidence that SLP-76 Y173 supports proximal TCR and FcεRI signaling; but its role in thymocyte development was never explored. Here we demonstrate that SLP-76 Y173 was required for TCR/CD28-induced degradation of IκB; moreover, both ITK and SLP-76 Y173 were required for persistent TCR-induced phosphorylation of PLC-γ1, ERK and p38. To explore whether SLP-76 Y173 may mediate ITK-dependent events in vivo, we replaced SLP-76 Y173 with phenylalanine in a mouse model. Like ITK-deficient thymocytes, SLP-76 Y173F thymocytes exhibited reduced thymic cellularity, reduced CD4/CD8 ratios, and reduced surface expression of CD5. In ex vivo-stimulated thymocytes, mutation of SLP-76 Y173 or inhibition of ITK reduced the persistence of TCR-induced calcium flux; moreover, TCR-induced phosphorylation of ERK and p38 depended on SLP-76 Y173. Like ITK-deficient thymi, SLP-76 Y173F thymocytes exhibited decreased production of CD4 − iNKT 1 thymocytes, coupled with increased production of innate-like CD4 + and CD8 + SP thymocytes. Our results provide strong evidence that the ITK substrate site, SLP-76 Y173, promotes TCR signal persistence that is required to mediate the thymic developmental effects of ITK. One Sentence Summary An ITK substrate site, SLP-76 Y173, is a predominant mediator of the signaling and developmental effects of ITK. Key Points An ITK substrate site, SLP-76 Y173, regulates TCR signal amplitude and persistence Persistent TCR-induced phosphorylation of p38 depends on ITK and SLP-76 Y173 The thymic developmental effects of ITK are predominantly mediated by SLP-76 Y173
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Award: G1683509472
OpenAlex ID: W7223964325