Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity.
The mechanisms governing positive selection of T cells in the thymus are still incompletely understood. Here, we describe a N-ethyl-N-nitrosourea induced recessive mouse mutant, Ms. T-less, which lacks T cells in the peripheral blood because of a complete block of thymocyte development at the CD4(+)CD8(+) stage. Single nucleotide polymorphism mapping and candidate gene sequencing revealed a nonsense mutation in the inositol (1,4,5) trisphosphate 3 kinase B (Itpkb) gene in Ms. T-less mice. Accordingly, Ms. T-less thymocytes do not show detectable expression of Itpkb protein and have drastically reduced basal inositol (1,4,5) trisphosphate kinase activity. Itpkb converts inositol (1,4,5) trisphosphate to inositol (1,3,4,5) tetrakisphosphate, soluble second messengers that have been implicated in Ca(2+) signaling. Surprisingly, Ca(2+) responses show no significant differences between wild type (WT) and mutant thymocytes. However, extracellular signal-regulated kinase (Erk) activation in response to suboptimal antigen receptor stimulation is attenuated in Ms. T-less thymocytes, suggesting a role for Itpkb in linking T cell receptor signaling to efficient and sustained Erk activation.
Wen
Ben G
BG
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Pletcher
Mathew T
MT
Warashina
Masaki
M
Choe
Sun Hui
SH
Ziaee
Niusha
N
Wiltshire
Tim
T
Sauer
Karsten
K
Cooke
Michael P
MP
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D020013:Calcium Signaling; D002478:Cells, Cultured; D018389:Codon, Nonsense; D004789:Enzyme Activation / Q000276:immunology; D005434:Flow Cytometry; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000254:growth & development / Q000276:immunology; D018631:ras Proteins / Q000378:metabolism
D015703:Antigens, CD; D018389:Codon, Nonsense; D011948:Receptors, Antigen, T-Cell; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins