INDUCTION OF APOPTOSIS AND T-HELPER-2 (TH2) RESPONSES CORRELATES WITHPEPTIDE AFFINITY FOR THE MAJOR HISTOCOMPATIBILITY COMPLEX IN SELF-REACTIVE T-CELL RECEPTOR TRANSGENIC MICE

Multiple sclerosis is an autoimmune disease thought to be mediated by CD4(+) T helper cells (Th). Experimental autoimmune encephalomyelitis is a rodent model of multiple sclerosis and has been used extensively to explore a variety of immunotherapies using soluble protein or pepti de antigens. The underlying mechanisms of such therapy have been attri buted to induction of T cell anergy, a switch in Th1 to Th2 responses, or peripheral deletion of autoreactive T cells. In this study, we hav e developed transgenic mice expressing a T cell receptor (TCR) specifi c for the NH2-terminal peptide Ac1-11 of the autoantigen myelin basic protein to explore the mechanism of soluble peptide therapy. T cells f rom these mice are highly skewed toward the CD4 population and have an abnormal thymic architecture, a phenomenon found in other TCR transge nic mice that exhibit a highly skewed CD4/CD8 ratio. Soluble Ac1-11 or the analogues Ac1-11[4A] or Ac1-11[4Y] (which bind to the major histo compatibility complex [MHC] class II molecule I-A(u) with increasing a ffinities) given intravenously activates T cells, rendering cells hype rresponsive in vitro for at least two days after injection. Concomitan tly, T cells apoptose in the periphery, the degree of which correlates with the affinity of the peptide for the MHC. In addition, a shift in the T helper phenotype of the surviving T cells occurs such that the low affinity peptide, Ac1-11, induces primarily a Th1 response, wherea s the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 ty pe response. These data show that both the nature and the presumed num ber of the peptide-MHC complexes formed during specific peptide therap y affect both the degree of peripheral programmed cell death as well a s the outcome of the T helper subset response in vivo, leading to amel ioration of disease.