Perturbed development of T and B cells in mice expressing an Hlx homeobox transgene.
Within the lymphoid compartment of mice, the Hlx homeobox gene is expressed only at early stages of B-lymphoid differentiation. To determine whether Hlx influences lymphopoiesis, transgenic mice were developed to enforce Hlx expression throughout the B and T cell lineages. The strain with the highest transgene expression in both cell types (Hlx-94) exhibited marked perturbations in both B and T cell development. In these mice, the thymus lacked almost all mature CD4+8- and CD8+4- cells and the medulla was greatly shrunken, whereas nearly one-half the T cells in the periphery were CD4+8+, a cell type normally confined to the thymus. The peripheral CD4+8+ cells had some features of mature T cells, including responsiveness to mitogens. Presumably these cells had emigrated prematurely from the thymus and generated mature T cells in the periphery. Bone marrow transplantation experiments indicated that the defects was intrinsic to the Hlx-94 hematopoietic cells rather than support cells. Although thymocyte development in Hlx-94 mice was blocked at the stage when selection normally occurs, analysis of lymphocyte populations in the progeny of crosses with mice transgenic for an anti-HY T cell receptor indicated that neither positive nor negative selection of T cells was markedly affected. In addition to T cell defects, Hlx-94 mice had subnormal numbers of B lymphoid cells in the bone marrow and spleen, and their surface phenotype suggested that B cell development after the pro-B stage was impeded. Furthermore, the B cell response to stimulation with LPS was impaired. These striking developmental defects suggest that the Hlx gene may help to govern lymphoid maturation.
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Melbourne, Australia.
J D
JD
Allen
A W
AW
Harris
M L
ML
Bath
A
A
Strasser
R
R
Scollay
J M
JM
Adams
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005801:Genes, Homeobox; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
C489999:Hlx protein, mouse; D018398:Homeodomain Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors