Abstract
Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected. PKD is activated in CD4+CD8+ double positive (DP) thymocytes on stimulation with positively selecting peptides. By phosphoproteomic analysis, we identify SH2-containing protein tyrosine phosphatase-1 (SHP-1) as a direct substrate of PKD. Substitution of wild-type SHP-1 by phosphorylation-defective mutant (SHP-1S557A) impairs generation of CD4+ thymocytes. These results suggest that the PKD–SHP-1 axis positively regulates TCR signalling to promote CD4+ T cell development.
Highlights
Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development
To obtain preselection thymocytes bearing antigen-specific TCR, bone marrow (BM) cells from OT-I TCR Tg mice were transferred into transporter associated with antigen processing (TAP)-deficient mice, which lack functional major histocompatibility complex (MHC) class I
protein kinase D (PKD) appears to control the generation of CD4 single positive (SP) thymocytes through promoting (i) TCR signalling during positive selection, and (ii) CD4 lineage specification
Summary
Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. W Present addresses: Max-Delbruck-Center for Molecular Medicine, Robert Rossel Street 10, 13125 Berlin, Germany (T.Y.); Department of Genetics, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya-shi, An appropriate ab T cell receptor (TCR) repertoire is shaped in the thymus through multiple selection steps In this process, transduction of signals through the TCR in CD4 þ CD8 þ double positive (DP) thymocytes determines CD4/CD8 lineage specification and generates CD4 þ CD8 À and CD4 À CD8 þ single positive (SP) thymocytes. No studies have addressed the role of PKD in thymocyte development using mice lacking all PKD isoforms, and the downstream substrates of PKD in thymocytes have not fully been elucidated Inhibitory signalling molecules, such as protein tyrosine phosphatases (PTPs), modulate TCR signalling and contribute to setting the threshold for thymocyte selection[16,17]. The role of serine/threonine phosphorylation in the function of SHP-1 remains unclear[23]
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