High level of cross-reactivity in influenza virus hemagglutinin-specific CD4+ T-cell response: implications for the initiation of autoimmune response in multiple sclerosis.
Viral infections play a role in shaping and maintaining the peripheral T-cell repertoire, as well as in the initiation of autoimmune response via mechanisms of molecular mimicry. In this study, we addressed the flexibility of T-cell receptor (TCR) recognition and the degree of structural and sequence homology required for cross-reactive immune response in the induction of autoimmune response. We studied the extent of cross-reactivity of a CD4+T-cell clone (TCC) specific for the immunodominant influenza virus hemagglutinin (Flu-HA) peptide derived from a patient with multiple sclerosis (MS) using positional scanning synthetic peptide combinatorial libraries (PS-SCL). We documented cross-reactivity against 14 Flu-HA variants, 11 viral, 15 human, and 3 myelin-derived peptides. Moreover, we identified six naturally occurring peptides with higher stimulatory potency than the native ligand, implicating high potential for cross-reactivity even for a virus-specific memory TCC. Our study demonstrates that flexibility of TCR recognition is present even in a clone with a high degree of TCR specificity for an infectious agent. The results have implications for vaccine design and for antigen-specific treatment strategies for autoimmune diseases.
Markovic-Plese
Silva
S
Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. markovics@neurology.unc.edu
Hemmer
Bernhard
B
Zhao
Yingdong
Y
Simon
Richard
R
Pinilla
Clemencia
C
Martin
Roland
R
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002999:Clone Cells; D003429:Cross Reactions; D030541:Databases, Genetic; D018604:Epitope Mapping; D006387:Hemagglutination, Viral / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D009185:Myelin Proteins / Q000378:metabolism; D009975:Orthomyxoviridae / Q000737:chemistry*; D019151:Peptide Library; D012372:ROC Curve
D009185:Myelin Proteins; D019151:Peptide Library