A COMPARISON OF ITEM SELECTION TECHNIQUES FOR NORM-REFERENCED AND CRITERION-REFERENCED TESTS.

Abstract

BCL11B is a transcription factor with six C₂H₂-type zinc-finger domains. Studies in mice have shown that Bcl11b plays essential roles in T cell development. Several germline heterozygous BCL11B variants have been identified in human patients with inborn errors of immunity (IEI) patients. Among these, two <i>de novo</i> mis-sense variants cause asparagine (N) to lysine (K) replacement in distinct zinc-finger domains, BCL11B^N441K and BCL11B^N807K. To elucidate the pathogenesis of the BCL11B^N807K variant, we generated a mouse model of BCL11B^N807K by inserting the corresponding mutation, <i>Bcl11b^N797K</i>, into the mouse genome. In <i>Bcl11b^+/N797K</i> mice, the proportion of immature CD4^-CD8⁺ single-positive thymocytes was increased, and the development of invariant natural killer cells was severely inhibited in a T-cell-intrinsic manner. Under competitive conditions, γδT cell development was outcompeted by control cells. <i>Bcl11b^N797K/N797K</i> mice died within one day of birth. Recipient mice reconstituted with <i>Bcl11b^N797K/N797K</i> fetal liver cells nearly lacked CD4⁺CD8⁺ double-positive thymocytes, which was consistent with the lack of their emergence in culture from <i>Bcl11b^N797K/N797K</i> fetal liver progenitors. Interestingly, <i>Bcl11b^N797K/N797K</i> progenitors gave rise to aberrant c-Kit⁺ and CD44⁺ cells both <i>in vivo</i> and <i>in vitro</i>. The increase in the proportion of immature CD8 single-positive thymocytes in the Bcl11b^N797K mutants is caused, in part, by the inefficient activation of the <i>Cd4</i> gene due to the attenuated function of the two <i>Cd4</i> enhancers via distinct mechanisms. Therefore, we conclude that immunodeficient patient-derived Bcl11b^N797K mutant mice elucidated a novel role for Bcl11b in driving the appropriate transition of CD4^-CD8^- into CD4⁺CD8⁺ thymocytes.