Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets

Significance The mechanisms through which successful immunotherapy induces possible deletion, replacement, or reprogramming of T cells are unknown. By evaluating the expression of T-cell–related genes, and using appropriate multivariate statistical approaches, our data show that successful immunotherapy can induce previously unidentified CD4+ T-cell subtypes during treatment that could help to predict an “immune-tolerant” clinical phenotype identified after cessation of treatment. The ability to use “anergic” transcriptional phenotypes in single T cells to predict successful “immune tolerance” induction in the clinic setting, as suggested by our findings, could lead to transformative impacts in the field of immunotherapy. Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional “roadmap” of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an “anergic” Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.

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