T-HELPER LYMPHOCYTES SPECIFIC FOR MYELIN BASIC-PROTEIN - ACTIVATION-INDUCED REFRACTORINESS OF IL-2 PRODUCTION PATHWAYS AUGMENTS AN ANTI-CD4-MEDIATED PROLIFERATIVE DEFICIT
Md. Mannie et al., T-HELPER LYMPHOCYTES SPECIFIC FOR MYELIN BASIC-PROTEIN - ACTIVATION-INDUCED REFRACTORINESS OF IL-2 PRODUCTION PATHWAYS AUGMENTS AN ANTI-CD4-MEDIATED PROLIFERATIVE DEFICIT, Cellular immunology, 154(2), 1994, pp. 484-497
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.