The Absence of Itk Inhibits Positive Selection

The Tec family tyrosine kinase Itk is critical for efficient signaling downstream of the TCR. Biochemically, Itk is directly phos-phorylated and activated by Lck. Subsequently, Itk activates phospholipase C-␥1, leading to calcium mobilization and extracel-lular signal-regulated kinase/mitogen-activated protein kinase activation. These observations suggested that Itk might play an important role in positive selection and CD4/CD8 lineage commitment during T cell development in the thymus. To test this, we crossed Itk-deficient mice to three lines of TCR transgenics and analyzed progeny on three different MHC backgrounds. Analysis of these mice revealed that fewer TCR transgenic T cells develop in the absence of Itk. In addition, examination of multiple T cell development markers indicates that multiple stages of positive selection are affected by the absence of Itk, but the T cells that do develop appear normal. In contrast to the defects in positive selection, CD4/CD8 lineage commitment seems to be intact in all the TCR transgenic itk ؊/؊ lines tested. Overall, these data indicate that altering TCR signals by the removal of Itk does not affect the appropriate differentiation of thymocytes based on their MHC specificity, but does impact the efficiency with which thymocytes complete their maturation process. T he development of mature T cells from thymic precursors is mediated in large part by signals downstream of TCR complexes. The largest population of immature T cells in the thymus are double positive (DP) 3 for the coreceptors CD4 and CD8, have productive TCR ␣-and ␤-chain gene rearrangements, and therefore express a mature TCR signaling complex on their surface. At this stage in development, thymocytes must undergo two concurrent, but distinct, developmental processes to become functional and tolerant mature T cells. One of these processes is known as repertoire selection, which ensures that mature T cells can recognize foreign peptides presented by self-MHC molecules, but will not become activated when they encounter self-peptide/ self-MHC complexes. The second process, lineage commitment, is the process by which thymocytes that recognize peptide in the context of MHC class I become CD8 ϩ cytotoxic T cell precursors, and thymocytes that recognize peptide in the context of MHC class II molecules become CD4 ϩ Th cell precursors. Both these processes are known to be dependent on TCR signaling; however, it has often been debated how the same initial signals can give rise to these different and opposing developmental outcomes. Current theories propose that the strength of the signal …