Evidence for early onset, polyclonal activation of T cell subsets in mice homozygous for lpr.
Mice homozygous for lpr and gld develop profound lymphadenopathy characterized by the accumulation of two functionally anergic T cell subsets, a predominant B220+CD4-CD8- double negative (DN) population and a minor, closely related CD4 dull+ B220+ population. Lymph nodes from diseased lpr and gld mice also contain abnormally high numbers of conventional T cells, and we reported recently that a high proportion of lpr and gld CD4+B220- T cells have the hallmarks of primed or memory T cells. In the present study, we further investigated the extent, ontogeny, and possible causes of T cell activation in lpr and gld mice. The criteria used to identify primed or memory T cells included activation-dependent increases in the expression of CD44, LFA-1, and the early activation Ag, CD69, and decreases in the expression of Mel-14 and CD45RB, as well as quantitative differences in the in vitro production of IFN-gamma and the TNF-alpha by stimulated cells. A comparison of TCR V beta gene utilization by lpr T cell subsets also was undertaken. The results showed that T cell activation was widespread and complex. CD8+ T cells exhibited a similar pattern of activation to CD4+B220- T cells. The activation of these two subsets occurred in parallel, was in evidence by 4 to 6 wk of age, and was both chronic and progressive. The proportions of CD44hiLFA-1hi, CD4+B220-, and CD8+ T cells increased steadily between 4 and 20 wk of age, but changes in T cell growth, Mel-14, and CD45RB expression and cytokine secretion were not observed until mice were older than 11 wk. A very different pattern of activation was observed for B220+ T cells. At all ages, B220+ DN and CD4+B220+ T cells were CD44hiMel-14hi and 60 to 75% were CD69+. The expression of CD69 appeared to be stimulus dependent rather than constitutive, suggesting that these cells, too, may be chronically stimulated in vivo. In keeping with their anergic state, DN T cells responded poorly to cross-linking of CD69. The stimuli inducing chronic activation of CD4+B220- and CD8+ T cells are unlikely to include inappropriate reactions to autoantigens because there was no evidence for selective accumulation of CD4+ or CD8+ T cells bearing particular V beta genes or potentially self-reactive cells that normally are deleted in the thymus. By comparison, C3H-lpr DN cells displayed some potentially significant differences in V beta 6 and V beta 9 expression from CD4+B220- and CD8+ T cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Giese
T
T
Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Davidson
W F
WF
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002469:Cell Separation; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis; D019041:L-Selectin; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D015815:Cell Adhesion Molecules; D007371:Interferon-gamma; D019041:L-Selectin; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens