Degenerate TCR recognition and dual DR2 restriction of autoreactive T cells: implications for the initiation of the autoimmune response in multiple sclerosis.
TCR degeneracy may facilitate self-reactive T cell activation and the initiation of an autoimmune response in multiple sclerosis (MS). MHC class II alleles of the DR2 haplotype DR2a (DRB5*0101) and DR2b (DRB1*1501) are associated with an increased risk for MS in Caucasian populations. In order to selectively expand and characterize T cells with a high degree of TCR degeneracy that recognize peptides in the context of disease-associated DR2 alleles, we developed DR2-anchored peptide mixtures (APM). We report here that DR2-APM have a high stimulatory potency and can selectively expand T cells with a degenerate TCR (TCR(deg)). Due to the low concentration of individual peptides in the mixtures, T cell clones' proliferative response to DR2-APM implies that multiple peptides stimulate the TCR, which is a characteristic of TCR(deg). The frequency of DR2-APM-reactive T cells is significantly higher in MS patients than in healthy controls, suggesting that they may play a role in the development of the autoimmune response in MS. DR2-APM-reactive cells have a dual DR2 restriction: they recognize DR2-APM in the context of both DR2a and DR2b molecules. The DR2-APM-reactive cells' IL-17 secretion, together with cross-reactivity against myelin peptides, may contribute to their role in the development of autoimmune response in MS.
Zhang
Xin
X
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
Tang
Yunan
Y
Sujkowska
Danuta
D
Wang
Jinzhao
J
Ramgolam
Vinod
V
Sospedra
Mireia
M
Adams
Jeremy
J
Martin
Roland
R
Pinilla
Clemencia
C
Markovic-Plese
Silva
S
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D015551:Autoimmunity / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015802:HLA-DR2 Antigen / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein / Q000276:immunology; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D015802:HLA-DR2 Antigen; D020381:Interleukin-17; C571326:MOG protein, human; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007371:Interferon-gamma