MHC-restriction, cytokine profile, and immunoregulatory effects of human T cells specific for TCR V beta CDR2 peptides: comparison with myelin basic protein-specific T cells.
HLA-DR2+ patients with multiple sclerosis (MS) that respond to vaccination with TCR V beta 5.2-38-58 peptides have increased frequencies of TCR peptide-specific T cells, reduced frequencies of myelin basic protein (MBP)-specific T cells, and a better clinical course than non-responders. To evaluate possible network regulation of MBP responses by TCR peptide-specific T cells, we compared properties of both cell types. Both MBP- and TCR peptide-specific T cell clones were CD4+ and predominantly HLA-DR restricted. HLA-DR2, which is in linkage disequilibrium in MS patients, preferentially restricted TCR peptide-specific clones as well as MBP-specific responses in HLA-DR2 and DR2,3+ donors. Within the DR2 haplotype, however, both DR beta 1*1501 and DR beta 5*0101 alleles could restrict T cell responses to V beta CDR2 peptides, whereas responses to MBP were restricted only by DR beta 5*0101. TCR peptide-specific clones expressed message for Th2 cytokines, including IL-4, IL-5, IL-6, IL-10, and TGF-beta, whereas MBP-specific T cell clones expressed the Th1 cytokines IFN-gamma and IL-2. Consistent with the Th2-like cytokine profile, TCR peptide-specific T cell clones expressed higher levels of CD30 than MBP-specific T cells. Culture supernatants from TCR peptide-specific T cell clones, but not from MBP- or Herpes simplex virus-specific T cells, inhibited both proliferation responses and cytokine message production of MBP-specific T cells. These results demonstrate distinct properties of MBP and TCR peptide-specific T cells, and indicate that both target and bystander Th1 cells can be inhibited by Th2 cytokines secreted by activated TCR peptide-specific T cells. These data support the rationale for TCR peptide vaccination to regulate pathogenic responses mediated by oligoclonal T cells in human autoimmune diseases.
Neuroimmunology Research Laboratory, Veterans Affairs Medical Center, Portland, OR 97201, USA.
Y K
YK
Chou
A D
AD
Weinberg
A
A
Buenafe
D N
DN
Bourdette
R
R
Whitham
J A
JA
Kaleeba
I F
IF
Robey
D G
DG
Kavanagh
H
H
Offner
A A
AA
Vandenbark
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000918:Antibody Specificity; D002999:Clone Cells; D016207:Cytokines / Q000097:blood*; D018984:Epitopes, T-Lymphocyte; D005260:Female; D006801:Humans; D008285:Major Histocompatibility Complex; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology*; D004676:Myelin Basic Protein / Q000097:blood*; D011948:Receptors, Antigen, T-Cell / Q000097:blood*; D018417:Th1 Cells
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein; D011948:Receptors, Antigen, T-Cell