Immunity to TCR peptides in multiple sclerosis. II. T cell recognition of V beta 5.2 and V beta 6.1 CDR2 peptides.

Abstract

The biased expression of V beta 5.2 and V beta 6.1 by T cells specific for myelin basic protein (BP) has led to our use of TCR peptides from these V gene sequences to induce anti-TCR immunity in patients with multiple sclerosis (MS). Injection of V beta 5.2-39-59 or V beta 6.1-39-59 peptides significantly increased the peptide specific T cell frequency in 7 of 11 MS patients, often with an accompanying delayed hypersensitivity reaction at the injection site. Here, we validate these cellular immune responses by characterizing TCR peptide specific T cells from an MS patient with biased V beta 5.2 expression in BP reactive T cells before treatment with TCR peptides, and from two MS patients in whom the frequencies of anti-TCR peptide specific T cells were significantly boosted after injection with low doses of TCR peptides. In both cases, T cell lines were established with relative ease, especially after boosting with the peptides. A V beta 5.2-39-59 reactive line responded selectively to the boosting peptide and was restricted by both MHC class I (HLA-B7) and MHC class II (HLA-DR2) molecules. Characterization of 22 clonal isolates revealed that the responding T cells were predominantly activated CD4+CD8lo, circulating memory cells restricted by either HLA-B7 or HLA-DR2, that utilized mainly V beta 4, V beta 6, V beta 12, and V beta 14, but not V beta 5.2 in their TCR. T cell isolates specific for V beta 6.1-39-59 possessed similar characteristics but contained specificities cross-reactive with an N-terminal sequence on V beta 5.2-39-59. Upon stimulation with peptide or Con A, the TCR peptide specific T cell lines had increased message production for IFN-gamma, GM-CSF, IL-4, IL-5, and to a lesser degree, IL-2. This lymphokine mRNA profile differed from a BP-specific T cell line that produced message for IFN-gamma and GM-CSF but low or absent levels of IL-4 and IL-5. The extensive parallels between human T cells specific for V beta 5.2 and V beta 6.1 CDR2 peptides and rat T cells specific for V beta 8.2 CDR2 peptide that are highly protective against experimental encephalomyelitis strengthen the rationale for the therapeutic use of TCR peptides in human autoimmunity.

• Authors: Y K Chou, W J Morrison, A D Weinberg, R Dedrick, R Whitham, D N Bourdette, G Hashim, H Offner, A A Vandenbark
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 152 Issue 5 Pg. 2520-9 (Mar 01 1994) ISSN: 0022-1767 [Print] United States
• PMID: 7510747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• Lymphokines
• Myelin Basic Protein
• Peptide Fragments
• RNA, Messenger
• Receptors, Antigen, T-Cell, alpha-beta

Topics

• Adult
• Aged
• Amino Acid Sequence
• Base Sequence
• Cell Line
• DNA Primers (genetics)
• Female
• Gene Expression
• Humans
• Immunotherapy
• Lymphokines (genetics)
• Male
• Middle Aged
• Molecular Sequence Data
• Multiple Sclerosis (immunology, therapy)
• Myelin Basic Protein (immunology)
• Peptide Fragments (genetics, immunology, therapeutic use)
• RNA, Messenger (genetics)
• Receptors, Antigen, T-Cell, alpha-beta (genetics, immunology)
• T-Lymphocytes (immunology)