Induction of peripheral tolerance with peptide-specific anergy in experimental autoimmune neuritis.
Neuritogenic T cells specific for SP-26, a synthetic peptide (residue 53-78) of myelin P2 protein that causes experimental autoimmune neuritis (EAN), use the same T cell receptor (TCR) V gene family (V beta 8) that can induce experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Tolerance to autoregulatory T cells may be induced in rats by intravenous (iv) administration of antigen-coupled splenocytes; however, the mechanisms that lead to altered immune reactivity are not well understood. Here we demonstrate that SP-26, when coupled to syngeneic spleen cells and administered iv, either before or after disease induction, markedly inhibited development and expression of clinical signs and histological changes of EAN. The induction of tolerance by this method was peptide-specific and MHC-restricted. We showed previously that T cells involved in EAN utilize the T cell antigen receptor V beta 8, whereas less than 5% of normal rat peripheral T cells express V beta 8. We have examined T lymphocytes from tolerized rats to determine the presence or absence of V beta 8(+)-bearing cells in order to determine the mechanism of tolerance. V beta 8 cells were undetectable by Northern blot analysis in the lymph nodes of unimmunized animals but easily detected in SP-26-primed and tolerized rats. In addition, spleen cells isolated from tolerized animals were anergic and failed to proliferate in response to SP-26, but retained responsiveness to IL-2 and Con A stimulation. Thus, the peptide-specific unresponsiveness that can be induced in rats with EAN, a T-cell-mediated process that is MHC-restricted and utilizes the T cell receptor V beta 8, occurs while V beta 8 transcripts remain readily detectable in spleen and lymph node cells. The detection of V beta 8-bearing T cells requires the development of antibodies specific for this rat surface protein.
Gregorian
S K
SK
Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia 19104.
Clark
L
L
Heber-Katz
E
E
Amento
E P
EP
Rostami
A
A
D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D007108:Immune Tolerance; D007114:Immunization; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology*; D018996:Myelin P2 Protein; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics
D004676:Myelin Basic Protein; D018996:Myelin P2 Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C076290:myelin P2 peptide SP26