The general aim of this project is to define the molecular basis of alternative commitment to the CD4 and CD8 T cell lineages during thymic development. A spontaneous autosomal recessive mutation has been identified in mice that specifically abrogates development of the CD4 T cell lineage causing a peripheral helper T cell deficiency (""""""""helper deficient,"""""""" or HD mice). Mutations at the CD4 and class II loci are specifically excluded as the cause of the phenotype, indicating that it represents a novel gene defect. The HD defect is transferred with cells of the hematopoietic lineage, and appears to be intrinsic to developing thymocytes. The current proposal addresses the following specific questions with regard to HD mice: 1) What are the developmental fates of class I- and II-restricted thymocytes in HD mice?, 2) Is the HD phenotype caused by a defect in stage- specific transcriptional regulation of the CD4 gene?, 3) Is mature T cell function impaired in HD mice, and if so is this due to alterations in TCR repertoire, T cell subset distribution or TCR-mediated signalling?, 4) What is the specific gene defect in HD mice? The proposed detailed phenotypic characterization of this unique mutant mouse and identification of the specific gene defect involved are expected to provide significant insights into the molecular mechanisms underlying lineage commitment.
| Engel, Isaac; Zhao, Meng; Kappes, Dietmar et al. (2012) The transcription factor Th-POK negatively regulates Th17 differentiation in V?14i NKT cells. Blood 120:4524-32 |
| Engel, Isaac; Hammond, Kirsten; Sullivan, Barbara A et al. (2010) Co-receptor choice by V alpha14i NKT cells is driven by Th-POK expression rather than avoidance of CD8-mediated negative selection. J Exp Med 207:1015-29 |
| Park, Kyewon; He, Xi; Lee, Hyung-Ok et al. (2010) TCR-mediated ThPOK induction promotes development of mature (CD24-) gammadelta thymocytes. EMBO J 29:2329-41 |
| He, Xi; Park, Kyewon; Wang, Haitao et al. (2008) CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus. Immunity 28:346-58 |
| He, Xiao; Kappes, Dietmar J (2006) CD4/CD8 lineage commitment: light at the end of the tunnel? Curr Opin Immunol 18:135-42 |
