ANERGY-ASSOCIATED T-CELL ANTIGEN PRESENTATION - A MECHANISM OF INFECTIOUS TOLERANCE IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

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.