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Requirement for Ca²⁺/Calmodulin-Dependent Kinase Type IV/Gr in Setting the Thymocyte Selection Threshold¹

Vidya Raman^*, Frank Blaeser^*, Nga Ho^*, Deborah L. Engle^*, Calvin B. Williams^* and Talal A. Chatila^2,*,,

Departments of ^* Pediatrics and Pathology and Immunology and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110

The outcome of thymocyte selection is influenced by the nature of Ca²⁺ signals transduced by the TCR. Robust Ca²⁺ responses characterize high-affinity, negatively selecting peptide/TCR interactions, while modest responses typify lower-affinity, positively selecting interactions. To elucidate mechanisms by which thymocytes decode distinct Ca²⁺ signals, we examined selection events in mice lacking Ca²⁺/calmodulin-dependent protein kinase type IV/Gr (CaMKIV/Gr), which is enriched in thymocytes. CaMKIV/Gr-deficient thymocytes exhibited impaired positive selection and defective Ca²⁺-dependent gene transcription. Significantly, CaMKIV/Gr deficiency raised the selection threshold of peptide/TCR interactions such that a peptide that normally induced weak negative selection instead promoted positive selection. These results demonstrate an important role for CaMKIV/Gr in sensitizing thymocytes to selection by low-affinity peptides.

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