title: Differential recognition of peptide analogs by naive verses activated PLP 139-151-specific CD4+ T cells.
abstract: CD4+ T cells specific for PLP 139-151 induce a relapsing-remitting form of EAE which is similar to the human demyelinating disease multiple sclerosis (MS) in both clinical course and histopathology. Conservative and nonconservative amino acid substitutions were introduced at three TcR or MHC contact residues within PLP 139-151 to identify fine specificity requirements, at the polyclonal level, for stimulating naive encephalitogenic T cells and for reactivating pre-primed autoreactive T cells as measured by T cell proliferation, cytokine induction, and functional encephalitogenic potential. The results indicate that peptides with substitutions at position 145 exhibited a significantly diminished ability to induce active disease, but these substitutions had little or no effect on the ability to activate PLP 139-151-primed T cells for proliferation or disease transfer. A conservative or a nonconservative substitution at position 144 ablated both encephalitogenic potential in active and adoptive EAE models and the ability to induce proliferative responses in T cells primed to the native peptide. A nonconservative lysine for glycine, but not a conservative serine substitution, at position 146 had similar effects. In contrast to their inability to induce active EAE and stimulate in vitro proliferation of PLP 139-151-primed T cells, the Y144 and the 146 analog peptides were able to suboptimally reactivate these cells for transfer of adoptive EAE. Furthermore, the nonencephalitogenic K146 peptide was found to exacerbate in vivo induction of EAE induced by priming with a suboptimal dose of PLP 139-151. These data support the hypothesis that naive neuroantigen-specific CD4+ T cells have more stringent activation requirements than do PLP 139-151-specific T cells which have previously encountered antigen. The finding that the analog peptides induced differential patterns of cytokine production, with LT/TNF-alpha production but not IFN-gamma production correlating with full encephalitogenic potential, suggests different functional outcomes may result from differential levels of signal transduction triggered by the substituted peptides. The significance of these results to the potential development of autoimmune disease via molecular mimicry and for the development of new strategies for preventing and treating T cell-mediated autoimmune diseases is discussed.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: McRae
authors.forename: K M
authors.initials: KM
authors.lastname: Nikcevich
authors.forename: W J
authors.initials: WJ
authors.lastname: Karpus
authors.forename: S D
authors.initials: SD
authors.lastname: Hurst
authors.forename: S D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D000939:Epitopes; D005260:Female; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009185:Myelin Proteins / Q000276:immunology*; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D012008:Recurrence; D012016:Reference Values
chemical_list: D000939:Epitopes; D008222:Lymphokines; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D010455:Peptides; C435023:myelin proteolipid protein (139-151)