T-HELPER LYMPHOCYTES SPECIFIC FOR MYELIN BASIC-PROTEIN - ACTIVATION-INDUCED REFRACTORINESS OF IL-2 PRODUCTION PATHWAYS AUGMENTS AN ANTI-CD4-MEDIATED PROLIFERATIVE DEFICIT

Cloned and uncloned lines of encephalitogenic rat T cells produce IL-2 when activated with myelin basic protein (MBP) in the presence of irr adiated splenocytes (SPL). Although these T cells use IL-2 as a primar y mediator of autocrine growth, regulatory mechanisms controlling prod uction of IL-2 have yet to be fully defined. This study shows that T c ells reactivated within similar to 7 days of a prior activation were r efractory to the reinduction of MBP-stimulated IL-2 production. In con trast, T cells rested for >7 days regained the ability to produce opti mal levels of IL-2 during activation with MBP. Cultures containing bot h activated and resting T cells responded to MBP by producing levels o f IL-2 that were similar to those obtained from control cultures of re sting T cells. The lack of IL-2 production during this refractory phas e was associated with lowered responsiveness to MBP in proliferative a ssays as evidenced by right-shifted dose-response curves. However, thi s refractory phase did not affect the magnitude of responses elicited by optimal concentrations of MBP. The dissociation of proliferation fr om IL-2 production suggested parallel pathways of autocrine growth. In deed, anti-MBP-proliferative responses were mediated by two distinct m echanisms distinguished by differential susceptibility to the anti-CD4 mAb W3/25. The W3/25-sensitive proliferation was desensitized in chro nically activated T cells as well as in T cells activated once in the presence of the anti-CD4 mAb W3/25. Conversely, MBP responsiveness of W3/25-insensitive proliferation was unchanged by both chronic activati on and by a prior activation in the presence of W3/25. In cultures of T cells recently activated by MBP in the presence of W3/ 25, the use o f nonirradiated SPL rather than irradiated SPL reversed W3/25-mediated tolerance but did not restore MBP-stimulated IL-2 production. In summ ary, this study reveals mechanisms whereby the engagement of TcR and C D4 negatively regulates subsequent responsiveness of IL-2 production p athways and thereby impairs restimulation of IL-2-dependent proliferat ion by MBP-specific T-helper cells. (C) 1994 Academic Press, Inc.