Article

HD mice: A novel mouse mutant with a specific defect in the generation of CD4+ T cells

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/1998; 95(14). DOI: 10.1073/pnas.95.14.8187
Source: PubMed Central

ABSTRACT We have identified a spontaneous mutation in mice, which we term HD for “helper T cell deficient.” This mouse is distinguished by the virtual absence of peripheral T cells of the CD4+8− major histocompatibility complex (MHC) class II-restricted T helper subset due to a specific block in thymic development. The developmental defect is selective for CD4+8− cells; the maturation of CD4−8+ and γδ T cells is normal. The autosomal recessive mutation underlying the HD phenotype is unrelated to MHC class II, since it segregates independently of the MHC class II locus. Moreover, the HD phenotype is not caused by a defect of the CD4 gene. Bone marrow transfer experiments demonstrate that the defect is intrinsic to cells of the hematopoietic lineage, i.e., most likely to developing thymocytes themselves. The frequency of CD4+8low intermediate cells is markedly increased in HD mice, suggesting that class II-restricted thymocytes are arrested at this stage. This is the first genetic defect of its kind to be described in the mouse and may prove highly informative in understanding the molecular pathways underlying lineage commitment.

Download full-text

Full-text

Available from: Richard Hardy, Aug 01, 2015
1 Follower
 · 
115 Views
  • Source
    • "It was thought that forced transgenic expression of CD4 coreceptors during positive selection rescued from cell death shortlived MHC-II signaled thymocytes that had stochastically made a CD8 lineage choice (Davis et al., 1993). However, this explanation and the presumptions underlying the stochastic/selection model have since been experimentally disproved (Adoro et al., 2008; Dave et al., 1998; Itano and Robey, 2000; Sarafova et al., 2005; Singer et al., 2008), leaving the generation of MHC-II specific CD8 + T cells in CD4 T3 transgenic mice unexplained. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The lineage fate of developing thymocytes is determined by the persistence or cessation of T cell receptor (TCR) signaling during positive selection, with persistent TCR signaling required for CD4 lineage choice. We show here that transcriptional upregulation of CD4 expression is essential for error-free lineage choice during major histocompatibility complex class II (MHC II)-specific positive selection and is critical for error-free lineage choice in TCR-transgenic mice whose thymocytes compete for the identical selecting ligand. CD4 upregulation occurred for endogenously encoded CD4 coreceptors, but CD4 transgenes were downregulated during positive selection, disrupting MHC II-specific TCR signaling and causing lineage errors regardless of the absolute number or signaling strength of transgenic CD4 proteins. Thus, the kinetics of CD4 coreceptor expression during MHC II-specific positive selection determines the integrity of CD4 lineage choice, revealing an elegant symmetry between coreceptor kinetics and lineage choice.
    Immunity 09/2009; 31(3):480-90. DOI:10.1016/j.immuni.2009.07.006 · 19.75 Impact Factor
  • Source
    • "There are two mutant strains that show T cell developmental defects whereby only CD4 + T cells, not CD8 + T cells, fail to develop properly. The HD mouse is one such mutant [3]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Long-Evans Cinnamon (LEC) rat has a spontaneous mutation, T helper immunodeficiency (thid), which causes a markedly reduced CD4(+) thymocyte population. Here we positionally clone the locus and identify a deletion in the gene encoding a receptor-like protein tyrosine phosphatase kappa (Ptprk) that led to complete loss of the transcript. The rat Ptprk gene exhibits 98% identity with the human and mouse counterparts and is expressed most abundantly in the CD4(-)CD8(-) double-negative stage. The downregulation of Ptprk in mouse immature thymocytes by RNA interference mimicked the thid phenotype. These results indicate that thid maps to the Ptprk locus and that functional Ptprk is crucial for lineage commitment or progression of CD4(+) T cells. We also found that Ptprk appears to function in parallel with or downstream of Th-POK/cKrox (also known as ZBTB7B), a master regulator of T cell lineage decision.
    Genomics 07/2007; 89(6):673-7. DOI:10.1016/j.ygeno.2007.03.001 · 2.79 Impact Factor
  • Source
    Nature · 42.35 Impact Factor
Show more