Abstract
Myelin basic protein (MBP)-specific T cells were isolated directly from peripheral blood by stimulation either with native MBPp85-99 or altered peptide ligands (APLs) in which substitutions of the lysine were made at position 93, a TCR contact residue. We report here that the APL 93A could alter the cytokine profile of some autoreactive MBPp85-99 reactive T cell clones, switching them from a Th0 phenotype secreting high concentrations of IL-4, IL-5, and IFN-gamma into Th2 cells secreting significantly less IFN-gamma. However, in vitro stimulation with the 93A peptide, in some instances, induced T cells that responded better to the native MBPp85-99 peptide. Functionally, the APL 93A was shown to act as an antagonist for IFN-gamma secretion. Based on TCR sequencing and single cell cloning, this alteration in cytokine profile was determined to be the result of the differential activation of individual T cell clones. We discuss the implications of these data for the strength of signal model of T cell activation.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Autoimmune Diseases / blood
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Autoimmune Diseases / immunology*
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Cell Differentiation / drug effects
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Cell Line
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Clone Cells
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Gene Rearrangement, T-Lymphocyte
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Humans
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Immunodominant Epitopes / chemistry
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Immunodominant Epitopes / immunology*
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Interferon-gamma / metabolism*
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Interleukin-4 / metabolism*
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Interleukin-5 / metabolism*
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Lymphocyte Activation
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Multiple Sclerosis / blood
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Multiple Sclerosis / immunology*
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Myelin Basic Protein / chemistry
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Myelin Basic Protein / immunology*
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Peptide Fragments / chemistry
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Peptide Fragments / immunology*
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Peptide Fragments / pharmacology
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Structure-Activity Relationship
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology*
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Th1 Cells / metabolism
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Th2 Cells / metabolism*
Substances
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Immunodominant Epitopes
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Interleukin-5
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Myelin Basic Protein
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Peptide Fragments
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Receptors, Antigen, T-Cell, alpha-beta
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myelin basic protein 85-99
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Interleukin-4
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Interferon-gamma