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.
Allen
J D
JD
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Melbourne, Australia.
Harris
A W
AW
Bath
M L
ML
Strasser
A
A
Scollay
R
R
Adams
J M
JM
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