WHERE, WHEN, AND HOW TO DETECT BIASED EXPRESSION OF DISEASE-RELEVANT V-BETA-GENES IN RATS WITH EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

The biased use of Vbeta8.2 and Vbeta6 in rats by encephalitogenic T ce lls specific for the S72-89 and S87-99 epitopes of guinea pig basic pr otein (Gp-BP) has allowed the use of anti-Vbeta antibodies and synthet ic TCR peptides for treatment of experimental autoimmune encephalomyel itis (EAE). Striking V gene biases also occur in human autoimmune dise ases, raising the question of to what degree these biases reflect pote ntially pathogenic T cells. To address this question, we evaluated the expression of the EAE-associated marker Vbeta8.2 and Vbeta6 molecules in the periphery, spinal cord (SC), and cerebrospinal fluid (CSF) dur ing the course of EAE, in unselected, IL-2-expanded, and Gp-BP-restimu lated populations. In CSF cells, there was a strong bias for the marke r Vbeta before the onset of EAE, but this bias was not enhanced by IL- 2, which skewed the CSF population to >80% CD8+ T cells. In SC, the ma rker Vbeta were expressed optimally during the onset of EAE, even in u nselected cells, and this bias could be enhanced sequentially by IL-2 expansion and Gp-BP restimulation. During the recovery phase, however, the marker Vbeta8.2 bias was obfuscated by the appearance of a hetero geneous Vbeta T cell population. Biased expression of the marker V gen es was not detected in unselected or IL-2-expanded peripheral cells at any time during EAE. These data suggest that peripheral T cells beari ng the disease-relevant V genes first appeared in CSF before disease o nset and then migrated to SC beginning on the first day of clinical si gns. During the recovery phase of the disease, these cells were dilute d by an influx of T cells bearing other Vbeta genes, requiring restimu lation with Gp-BP to observe the Vbeta8.2 bias. These data have import ant implications for the interpretation of Vbeta gene biases that have been reported in human autoimmune diseases.