Md. Mannie et al., ANERGY-ASSOCIATED T-CELL ANTIGEN PRESENTATION - A MECHANISM OF INFECTIOUS TOLERANCE IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, The Journal of immunology, 157(3), 1996, pp. 1062-1070
CD4(+) T cells promote immune responses against foreign Ags while acti
vely suppressing responses against self Ags. To address how CD4(+) T c
ells ensure self-tolerance, we focused on two CD4(+) T helper cells sp
ecific for myelin basic protein (MBP). GP2.E5/R1 T cells recognized ra
t MBP (RMBP) as a partial agonist and mediated mild experimental autoi
mmune encephalomyelitis myelitis (EAE), whereas R2 T cells recognized
RMBP with full efficacy and mediated severe EAE. GP2.E5/R1 T cells wer
e more susceptible to anergy induction than R2 T cells. Anergic GP2.E5
/R1 T cells lacked proliferative reactivity, but expressed both I-A gl
ycoproteins and high levels of radioresistant APC activity. During ind
uction of anergy, these T cells acquired the ability to present MBP. I
n a separate subsequent culture without further addition of Ag, anergi
c GP2.E5/R1 T cells elicited full proliferative and IL-2 production re
sponses by R2 T cells. Unlike activations induced via irradiated splen
ocytes, irradiated anergic T cells elicited anergy in R2 T cells in th
e form of a postactivational phase of nonresponsiveness. Anergic GP2.E
5/R1 T cells not only transferred anergy to pathogenic R2 T cells in v
itro, but these anergic T cells also transferred resistance to EAE in
Lewis rats subsequently challenged with guinea pig MBP in CFA. Antagon
istic signaling by autologous RMBP was more tolerogenic than that of g
uinea pig MBP in both in vitro and in vivo models of infectious anergy
. We conclude that in the presence of tolerogenic mAb, antagonistic si
gnaling by a self protein elicited the coordinate expression of anergy
and T cell-mediated APC activity as a mechanism for the genesis and s
pread of infectious tolerance.