Ms. T-less, an ENU-induced mouse mutant linking impaired expression of Ins(1,4,5)P-3 3-kinase B (Itpkb) to defective Erk activation and blocked positive selection

The mechanisms governing positive selection of T cells are still incompletely understood. Here, we describe Ms. T-less, a novel recessive mouse mutant which lacks peripheral T cells due to a block of thymocyte development at the CD4(+)CD8(+) (DP) stage. Mutants harbor a nonsense codon early in the Ins(1,4,5)P-3 3-kinase B (Itpkb) gene, resulting in absence of full length Itpkb protein and reduced Itpk activity in thymocytes. Itpkb converts Ins(1,4,5)P-3 (IP3) to Ins(1,3,4,5)P-4 (IP4), both mediators of Ca2+ signaling. Surprisingly, Ca2+ responses did not differ significantly between wt and mutant thymocytes. In contrast, anti-CD3 induced Erk activation was strongly reduced in Ms. T-less thymocytes, suggesting a novel and essential role for Itpkb in linking TCR signaling to Erk activation.