Double-negative (L3T4-, Lyt2-) thymocytes of autoimmune lpr/lpr mice are resistant to down-regulation of DNA synthesis by a thymic stromal cell product.
The murine autosomal recessive gene, lpr, induces a progressive lymphadenopathy and lupus-like autoimmune syndrome characterized by the accumulation of immature, dull Thy 1.2+, TCR+, L3T4-/Lyt 2- (double-negative, DN) T cells in peripheral lymphoid organs. Previous studies demonstrated that the thymic microenvironment is required for the generation of the abnormal, peripheral DN T cells, while a more recent report linked the lpr gene defect with a failure of thymocytes to express a functional form of the Fas antigen, which mediates apoptosis. Thus, the lpr gene defect apparently prevents lpr thymocytes from responding to the ordered sequence of differentiation and proliferation signals involved in normal thymocyte maturation and selection. We compared the responses of thymocytes from C57BL/6 +/+ (normal) and congenic C57BL/6 lpr/lpr (lpr) mice to a thymic stromal cell product which down-regulates DNA synthesis in vitro. The results indicate that (a) thymic stromal cells from lpr mice produce a factor that can down-regulate DNA synthesis as efficiently as that from normal mice, even at an age when massive lymphadenopathy is present, (b) mitogen-stimulated thymocytes of normal, but not lpr, mice are sensitive to the inhibitory factor, (c) normal DN thymocytes are the cellular target of the inhibitory factor, which acts at some postmembrane receptor-ligand binding event during mitogen-stimulated proliferation, and (d) IL-4-dependent DN thymocyte proliferation seems to be the main target of the inhibitory factor.
Lubinski
J M
JM
Geriatric Research, Education and Clinical Center (GRECC), VA Medical Center West Los Angeles, California 90073.
James
S J
SJ
Nakamura
L T
LT
Serrano-Williams
A
A
Munekata
M T
MT
Ho
S C
SC
Chung
J C
JC
Makinodan
T
T
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D000950:Antigens, Ly / Q000032:analysis*; D001327:Autoimmune Diseases / Q000276:immunology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D015536:Down-Regulation; D006131:Growth Inhibitors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017154:Stromal Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D006131:Growth Inhibitors; D004247:DNA