Distinctive gene signature of allergen-specific CD4+T cells in allergic patients

Allergic patients display abnormal immune responses to harmless antigens, including abnormal Th2 polarization and induction of allergen-specific T and B cells, resulting in development of allergy instead of tolerance. Allergen-specific immunotherapy (AIT) is currently the only causative treatment of allergic disorders. Yet, understanding of the underlying differences in allergen-specific responses between allergy and tolerance is lacking. We investigated whole-genome transcriptomics of circulating birch and grass specific CD4+ T cells in patients before and during AIT, as well in non-allergic healthy controls. Detailed immunophenotyping with flow cytometry and CD4+ MHC class II tetramer staining with low RNA/single cell next generation sequencing were performed. At baseline, out of the season, there were more allergen-specific CD4+ T cells in allergic patients than in controls. At this time, over 1500 genes were differently expressed in allergen-specific CD4+T cells in patients, but they were less upregulated in signal transduction, inflammatory response and coagulation categories as compared to controls. During AIT we noted further increase of allergen-specific CD4+ cells with subsequent gene expression change. Finally, we found increase in allergen-specific Treg cells in patients upon AIT, but not in tolerant controls. Yet, at early AIT time points, allergen-specific Treg cells displayed gene profiles suggesting their insufficient functions. In summary, in vivo allergen exposure causes profound changes in the transcriptomic profiles of allergen-specific T cells. These gene profiles seem to be deficient at baseline in allergic patients, but AIT is skewing them into the tolerant controls levels.