Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4+ T cell epitopes with other tree nuts

Summary Background Allergies to cashew are increasing in prevalence, with clinical symptoms ranging from oral pruritus to fatal anaphylactic reaction. Yet, cashew‐specific T cell epitopes and T cell cross‐reactivity amongst cashew and other tree nut allergens in humans remain uncharacterized. Objectives In this study, we characterized cashew‐specific T cell responses in cashew‐allergic subjects and examined cross‐reactivity of these cashew‐specific cells towards other tree nut allergens. Methods CD154 up‐regulation assay was used to determine immunodominance hierarchy among cashew major allergens at the T cell level. The phenotype, magnitude and functionality of cashew‐specific T cells were determined by utilizing ex vivo staining with MHC class II tetramers. Dual tetramer staining and proliferation experiments were used to determine cross‐reactivity to other tree nuts. Results CD4+ T cell responses were directed towards cashew allergens Ana o 1 and Ana o 2. Multiple Ana o 1 and Ana o 2 T cell epitopes were then identified. These epitopes elicited either TH2 or TH2/TH17 responses in allergic subjects, which were either cashew unique epitope or cross‐reactive epitopes. For clones that recognized the cross‐reactive epitope, T cell clones responded robustly to cashew, hazelnut and/or pistachio but not to walnut. Conclusions Phylogenetically diverse tree nut allergens can activate cashew‐reactive T cells and elicit a TH2‐type response at an epitope‐specific level. Clinical relevance Lack of cross‐reactivity between walnut and cashew suggests that cashew peptide immunotherapy approach may not be most effective for walnut.