A subset of CD4+ T cells expressing early activation antigen CD69 in murine lupus: possible abnormal regulatory role for cytokine imbalance.
Systemic lupus erythematosus (SLE), which spontaneously develops in (NZB (New Zealand Black) x NZW (New Zealand White)) F1 mice, is strictly dependent on CD4+ T cells. We found that in these mice with overt SLE, CD4+ T cells expressing CD69 molecules, an early activation Ag, are dramatically increased in peripheral lymphoid tissues and inflammatory infiltrates in the kidney and lung, but not in peripheral blood, while CD8+ and NK1.1+ T cells were virtually CD69-. Various adhesion molecules, including LFA-1, ICAM-1, CD43, CD44, P-selectin, and E-selectin, were up-regulated. Analysis of the TCR repertoire showed no skewed TCR Vbeta usage. Studies on in vitro cytokine production of spleen cells on TCR cross-linking indicated that compared with findings in young mice, the aged mice showed severely impaired production of IL-2, IL-3, and IL-4, whereas the levels of IL-10 and IFN-gamma remained relatively intact. FACS-sorted CD69-CD4+ T cells from aged mice produced substantial amounts of these cytokines, including IL-2, IL-3, and IL-4, whereas CD69+CD4+ T cells were poor producers. Intriguingly, when cocultured, CD69+CD4+ T cells significantly inhibited the production of IL-2 by CD69-CD4+ T cells. IL-2 production by spleen cells from young mice was also markedly inhibited in the presence of CD69+CD4+ T cells obtained from aged mice. We propose that CD69+CD4+ T cells that are continuously activated by self peptides bound to MHC class II molecules in (NZB x NZW)F1 mice may be involved in the pathogenesis of SLE through abnormal regulatory effects on cytokine balance.
Ishikawa
S
S
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Akakura
S
S
Abe
M
M
Terashima
K
K
Chijiiwa
K
K
Nishimura
H
H
Hirose
S
S
Shirai
T
T
D000367:Age Factors; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D037181:Lectins, C-Type; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008814:Mice, Inbred NZB; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D037181:Lectins, C-Type; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000099192:CD69 Antigens