Characterization of HLA class II/peptide-TCR interactions of the immunodominant T cell epitope in Art v 1, the major mugwort pollen allergen.
More than 95% of mugwort pollen-allergic individuals are sensitized to Art v 1, the major allergen in mugwort pollen. Interestingly, the CD4 T cell response to Art v 1 involves only one single immunodominant peptide, Art v 1(25-36) (KCIEWEKAQHGA), and is highly associated with the expression of HLA-DR1. Therefore, we investigated the molecular basis of this unusual immunodominance among allergens. Using artificial APC expressing exclusively HLA-DRB1*0101 and HLA-DRA*0101, we formally showed that DR1 acts as restriction element for Art v 1(25-36)-specific T cell responses. Further assessment of binding of Art v 1(25-36) to artificial HLA-DR molecules revealed that its affinity was high for HLA-DR1. Amino acid I27 was identified as anchor residue interacting with DR molecules in pocket P1. Additionally, Art v 1(25-36) bound with high affinity to HLA-DRB1*0301 and *0401, moderately to HLA-DRB1*1301 and HLA-DRB5*0101, and weakly to HLA-DRB1*1101 and *1501. T cell activation was also inducible by Art v 1(25-36)-loaded, APC-expressing HLA molecules other than DR1, indicating degeneracy of peptide binding and promiscuity of TCR recognition. Specific binding of HLA-DRB1*0101 tetramers containing Art v 1(19-36) allowed the identification of Art v 1(25-36)-specific T cells by flow cytometry. In summary, the immunodominance of Art v 1(25-36) relies on its affinity to DR1, but is not dictated by it. Future investigations at the molecular HLA/peptide/TCR and cellular level using mugwort pollen allergy as a disease model may allow new insights into tolerance and pathomechanisms operative in type I allergy, which may instigate new, T cell-directed strategies in specific immunotherapy.
Jahn-Schmid
Beatrice
B
Institute of Pathophysiology, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria. beatrice.jahn-schmid@meduniwien.ac.at
Sirven
Philémon
P
Leb
Victoria
V
Pickl
Winfried F
WF
Fischer
Gottfried F
GF
Gadermaier
Gabriele
G
Egger
Matthias
M
Ebner
Christof
C
Ferreira
Fatima
F
Maillére
Bernard
B
Bohle
Barbara
B
D000485:Allergens / Q000276:immunology*; D017951:Antigen Presentation; D019306:Artemisia / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte; D015798:HLA-DR1 Antigen; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D010446:Peptide Fragments / Q000276:immunology*; D011058:Pollen / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*
D000485:Allergens; D018984:Epitopes, T-Lymphocyte; D015798:HLA-DR1 Antigen; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell