Requirement for Ca2+/calmodulin-dependent kinase type IV/Gr in setting the thymocyte selection threshold.
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.
Raman
V
V
Departments of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Blaeser
F
F
Ho
N
N
Engle
D L
DL
Williams
C B
CB
Chatila
T A
TA
D000818:Animals; D001947:Breeding; D002118:Calcium / Q000502:physiology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D018507:Gene Expression Regulation, Developmental / Q000276:immunology; D006182:H-Y Antigen / Q000235:genetics; D006454:Hemoglobins / Q000235:genetics; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism
D006182:H-Y Antigen; D006454:Hemoglobins; D011948:Receptors, Antigen, T-Cell; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; D002118:Calcium