ANTIGEN-SPECIFIC DOWN-REGULATION OF MYELIN BASIC PROTEIN-REACTIVE T-CELLS DURING SPONTANEOUS-RECOVERY FROM EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS - FURTHER EVIDENCE OF APOPTOTIC DELETION OF AUTOREACTIVE T-CELLS IN THE CENTRAL-NERVOUS-SYSTEM

Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by the i.v, injection of 10(7) cloned V(beta)8.2(+) T cells specific for the 72-89 peptide of guinea pig myelin basic protein (MBP). Some animals were injected simultaneously with 10(7) cloned T cells specific for ovalbumin (OVA), Lymphocytes were isolated from the spinal cord and from the peripheral lymphoid organs of these rats and the frequencies of MBP-peptide-specific or OVA-specific proliferating cells were estimated by limiting dilution analysis at different times after cell transfer, The frequencies of cells specific for MBP(72-89) or OVA in the spinal cord were highest 5 days after cell transfer (MBP(72-88), 1 in 1149; OVA, 1 in 1116). On day 7, when the rats were recovering, the frequency of cells specific for MBP(72-89) in the spinal cord fell dramatically to <1 in 10(5), while that of OVA-specific cells decreased to a much lesser extent(1 in 7001). The frequencies of MBP(72-89)-specific cells in the peripheral lymphoid organs during and after recovery were also much lower than those of OVA-specific cells. A similar pattern of down-regulation of the MBP-peptide-specific, but not the OVA-specific, T cell response was observed in the spleen and mesenteric lymph nodes (MLN) of rats 38 days after the active induction of EAE by immunization with equal amounts of MBP and OVA in adjuvants, In the passively transferred model, cells isolated from the spinal cord and MLN on day 7 did not regain responsiveness to MBP(72-89) after incubation with high levels of IL-2, indicating that the unresponsiveness was not due to T cell anergy. Thus this study demonstrates that there is a specific down-regulation of the MBP(72-89)-specific T cell response during spontaneous recovery from EAE, This conclusion is consistent with our previous observation that V(beta)8.2(+) T cells are selectively eliminated from the CNS by apoptosis during recovery from EAE induced by the passive transfer of V(beta)8.2(+) T cells reactive to this MBP peptide. In contrast to autoreactive T cells, the non-autoreactive T cells that accumulate in the CNS during EAE appear to recirculate to the peripheral lymphoid organs.