Abstract
CD5 is well recognized for its importance in thymic selection. Although this property of CD5 has been attributed to its ITIM-domain dependent regulation of TCR-signal strength, the mechanism has not been established. A second major signaling domain within the cytoplasmic tail of CD5 is a CK2 binding/activation domain (CD5-CK2BD). Using a gene-targeted mouse in which the CD5-CK2BD is selectively ablated (CD5-ΔCK2BD), we determined that loss of function of CD5-CK2 signaling in a MHC-II selecting TCR transgenic (OT-II) mouse resulted in decrease in double positive (DP) thymocytes, which correlated with enhanced apoptosis. Remarkably, DP cells expressing high levels of CD5 and CD69 and single positive (CD4+SP) thymocytes were increased in CD5-ΔCK2BD mice indicating that CD5-CK2 signaling regulates positive selection and promotes survival. Consistent with this possibility, we determined that the activation and nuclear localization of ERK as well as apoptosis was greater in thymic populations from OTII CD5-ΔCK2BD mice than OTII CD5-WT mice following injection of OVA323-339-peptide. The mobilization of Ca2+, an early event of TCR activation, was not altered by the loss of CD5-CK2 signaling. Collectively, these data demonstrate that the CD5-CK2 signaling axis regulates positive selection by modulating activation of ERK and promoting survival independent of proximal TCR signals.
Highlights
T cell differentiation in the thymus is a developmental process tightly regulated by key selection checkpoints, which ensures the generation of a diverse self-restricted and autotolerant T cell repertoire
Using a gene-targeted mouse in which the CD5-CK2BD is selectively ablated (CD5-ΔCK2BD), we determined that loss of function of CD5-CK2 signaling in a MHC-II selecting TCR transgenic (OT-II) mouse resulted in decrease in double positive (DP) thymocytes, which correlated with enhanced apoptosis
We examined the contribution of CD5-CK2 signaling in thymic development by breeding the CD5-ΔCK2BD mouse with the TCROVA transgenic (OTII) mouse
Summary
T cell differentiation in the thymus is a developmental process tightly regulated by key selection checkpoints, which ensures the generation of a diverse self-restricted and autotolerant T cell repertoire. During this process, TCR mediated signaling has a central role in the final outcome of a functional T cell repertoire, whereby recognition of self-MHC/peptides complexes with low affinity/avidity rescues developing T cells from apoptosis by positive selection, while. Role of CD5-Associated CK2 in Thymocyte Selection
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