FUNCTIONAL HETEROGENEITY OF L3T4+ T CELLS IN MRL-lpr/lpr MICE L3T4+ T Cells Suppress Major Histocompatibility Complex-self-restricted L3T4+ T Helper Cell Function in Association with Autoimmunity BY CHARLES S. VIA AND GENE M. SHEARER

MRL/MpJ-lpr/lpr (MRL/1)t mice develop a disease similar to human SLE, consisting of massive lymphoproliferation, autoantibody production, and an immune complex glomerulonephritis that results in a 50% mortality by -20 wk of age (1-3). Congenic MRL/MpJ +/+ (MRL/+) mice share >98% of their genome with MRL/l mice but lack the gene for lymphoproliferation (lpr) (1, 3) . As a result, MRL/+ mice do not develop the massive lymphadenopathy characteristic of MRL/1 mice . Autoimmunity in MRL/+ mice is milder and occurs later in life, making them a useful control strain for MRL/l mice. The lupus-like disease of MRL/1 mice is thought to be primarily due to a disorder of T cells based on the following observations : (a) the massive lymphadenopathy induced by the lpr gene consists primarily ofTcells with an unusual phenotype (Thy 1 .2+, L3T4 , Lyt2 , Ly-5+, B220+ ) (4, 5) ; (b) neonatal thymectomy retards all aspects of the disease (6, 7) ; (c) in vivo depletion of Thy-1 .2 + or L3T4 + T cells improves disease (8, 9) ; and (d) MRL/1 T cells spontaneously produce factors that induce B cell differentiation and Ig secretion (10, 11) . Aparadoxical aspect ofthis model is that, despite the evidence for increased Th activity for B cells (10, 11), Th activity for T cell responses (e.g ., IL-2 production, IL-2 responsiveness, and in vitro CTL generation) has been reported to be reduced (12-14) . In the present study, we demonstrate that MRL/1 mice, and not MRL/+ mice, have an age-dependent loss of Th function that involves MHC-self-restricted L3T4 + Th responses and not Lyt-2+ Th responses . Associated with this defect is the appearance of suppressor cell activity that selectively inhibits L3T4+ MHC-selfrestricted responses. We have previously reported similar suppressor cell activity in two murine graft-vs .-host (GVH) models of autoimmunity (also characterized by excessive Th activity for B cells) (15-17), suggesting that these suppressor cells represent a common immunoregulatory mechanism in the setting ofautoimmunity.