A SUBSET OF CD4(-CELLS EXPRESSING EARLY ACTIVATION ANTIGEN CD69 IN MURINE LUPUS - POSSIBLE ABNORMAL REGULATORY ROLE FOR CYTOKINE IMBALANCE() T)

Systemic lupus erythematosus (SLE), which spontaneously develops in (N ZB (New Zealand Black) x NZW (New Zealand White)) F-1 mice, is strictl y 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 inflamm atory infiltrates in the kidney and lung, but not in peripheral blood, while CD8(+) and NK1.1(+) T cells were virtually CD69(-). Various adh esion molecules, including LFA-1, ICAM-1, CD43, CD44, P-selectin, and E-selectin, were up-regulated. Analysis of the TCR repertoire showed n o skewed TCR VP usage. Studies on in vitro cytokine production of sple en 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-IO and IFN-gamma remained r elatively intact. FAGS-sorted CD69(-)CD4(+) T cells from aged mice pro duced substantial amounts of these cytokines, including IL-2, IL-3, an d IL-4, whereas CD69(+)CD4(+) T cells mere poor producers. Intriguingl y, when cocultured, CD69(+)CD4(+) T cells significantly inhibited the production of IL-2 by CD69-CD4+ T cells. IL-2 production by spleen cel ls 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 M HC class II molecules in (NZB x NZW)F-1 mice may be involved in the pa thogenesis of SLE through abnormal regulatory effects on cytokine bala nce.