title: Induction of apoptosis and T helper 2 (Th2) responses correlates with peptide affinity for the major histocompatibility complex in self-reactive T cell receptor transgenic mice.
abstract: 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 peptide antigens. The underlying mechanisms of such therapy have been attributed to induction of T cell anergy, a switch in Th1 to Th2 responses, or peripheral deletion of autoreactive T cells. In this study, we have developed transgenic mice expressing a T cell receptor (TCR) specific for the NH2-terminal peptide Ac1-11 of the autoantigen myelin basic protein to explore the mechanism of soluble peptide therapy. T cells from these mice are highly skewed toward the CD4 population and have an abnormal thymic architecture, a phenomenon found in other TCR transgenic mice that exhibit a highly skewed CD4/CD8 ratio. Soluble Ac1-11 or the analogues Ac 1-11 [4A] or Ac1-11[4Y] (which bind to the major histocompatibility complex [MHC] class II molecule I-Au with increasing affinities) given intravenously activates T cells, rendering cells hyperresponsive in vitro for at least two days after injection. Concomitantly, 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, whereas the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 type response. These data show that both the nature and the presumed number of the peptide-MHC complexes formed during specific peptide therapy affect both the degree of peripheral programmed cell death as well as the outcome of the T helper subset response in vivo, leading to amelioration of disease.
authors.affiliation: Department of Microbiology and Immunology, Stanford University Medical Center, California 94305, USA.
authors.forename: C I
authors.initials: CI
authors.lastname: Pearson
authors.forename: W
authors.initials: W
authors.lastname: van Ewijk
authors.forename: H O
authors.initials: HO
authors.lastname: McDevitt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D016516:CD4-CD8 Ratio; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D010455:Peptides; D011948:Receptors, Antigen, T-Cell