title: Molecular determinants of T cell epitope recognition to the common Timothy grass allergen.
abstract: We investigated the molecular determinants of allergen-derived T cell epitopes in humans utilizing the Phleum pratense (Timothy grass) allergens (Phl p). PBMCs from allergic individuals were tested in ELISPOT assays with overlapping peptides spanning known Phl p allergens. A total of 43 distinct antigenic regions were recognized, illustrating the large breadth of grass-specific T cell epitopes. Th2 cytokines (as represented by IL-5) were predominant, whereas IFN-gamma, IL-10, and IL-17 were detected less frequently. Responses from specific immunotherapy treatment individuals were weaker and less consistent, yet similar in epitope specificity and cytokine pattern to allergic donors, whereas nonallergic individuals were essentially nonreactive. Despite the large breadth of recognition, nine dominant antigenic regions were defined, each recognized by multiple donors, accounting for 51% of the total response. Multiple HLA molecules and loci restricted the dominant regions, and the immunodominant epitopes could be predicted using bioinformatic algorithms specific for 23 common HLA-DR, DP, and DQ molecules. Immunodominance was also apparent at the Phl p Ag level. It was found that 52, 19, and 14% of the total response was directed to Phl p 5, 1, and 3, respectively. Interestingly, little or no correlation between Phl p-specific IgE levels and T cell responses was found. Thus, certain intrinsic features of the allergen protein might influence immunogenicity at the level of T cell reactivity. Consistent with this notion, different Phl p Ags were associated with distinct patterns of IL-5, IFN-gamma, IL-10, and IL-17 production.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Oseroff
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Maya F
authors.initials: MF
authors.lastname: Kotturi
authors.forename: Ravi
authors.initials: R
authors.lastname: Kolla
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Wasserman
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.forename: Denise M
authors.initials: DM
authors.lastname: McKinney
authors.forename: Jo L
authors.initials: JL
authors.lastname: Chung
authors.forename: Arnd
authors.initials: A
authors.lastname: Petersen
authors.forename: Howard
authors.initials: H
authors.lastname: Grey
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000485:Allergens / Q000276:immunology*; D000595:Amino Acid Sequence; D052179:Antigens, Plant / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology*; D031784:Phleum / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D052179:Antigens, Plant; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D020381:Interleukin-17; D015848:Interleukin-5; D009842:Oligopeptides; D016753:Interleukin-10; D007371:Interferon-gamma