Thymic-specific Regulation Of TCR Signaling By Tespa1

Double positive(DP)thymocytes undergo positive selection to become mature CD4+or CD8 single positive T cells under the instruction of T-cell receptor(TCR)signal.Unlike mature T-cells,DP cells are required to respond to low affinity self-peptide-MHC ligands before full upregulation of their surface TCR expression.Thus,DP thymocytes nust be more sensitive to ligand than mature T-cells.A number of molecules have been found to be able to augment the strength of the TCR signal to facilitate positive selection.However,almost all of them are also active in mature T-cells.Themis(thymocyte-expressed molecule involved in selection)and Tespal(thymocyte-expressed positive selection associated 1),are two newly defined molecules essential for optimal TCR signaling and thymocyte development.The deficiency of either molecule leads to defects in positive selection.Here we compared their relative contributions in thymocytes during positive selection.We show that Tespal deficiency led to more confined and specific gene expression profile changes in cells undergoing positive selection.In mixed bone manrow transfer experiments,Tespa1-/-cells displayed more severe defects in thymocyte development than Themis-/-cells.However,Tespa1-/-cells exerted a substantial degree of homeostatic expansion and became dominant in peripheral lymphoid organs,suggesting Tespa1 is a thymic-specific TCR signaling regulator.This hypothesis is further supported by our observations in Tespal conditional knockout mice,as Tespal deletion in peripheral T-cells didn't affect TCR signaling and cell proliferation.The differential regulatory roles of Tespal and Themis is in accordance with their nonredundant roles in thymocyte selection,wherein Tespa1 and Themis double knockouts showed additive defects.