Development of a pediatric immune cell atlas and characterization of CD4 + T cells in food allergy

Abstract The immune system undergoes maturation throughout early life, shaped partly by environmental exposures. As a result, pediatric immune responses can be implicated in many diseases including food allergy (FA). This study leveraged publicly available single‐cell RNA‐sequencing (scRNA‐seq) data from eight clinical studies analyzing peripheral blood mononuclear cells to develop a pediatric single‐cell reference atlas from 57 individuals. The atlas was used to investigate cellular heterogeneity between healthy children, characterize CD4+ T cells, and CD4+ T cell sub‐type specific responses associated with age and allergy. Seven CD4+ T cell subclusters were identified and annotated, a unique subset of cytotoxic Th2‐like cells was enriched for both peanut‐ and egg‐allergic gene signatures. Cluster‐specific age‐associated signatures were identified using multi‐variate regression models revealing enrichment of metabolic pathways during early‐life. FA gene signatures were identified using bulk and scRNA‐seq data and were compared across studies using the developed reference. Finally, Random Forest models were developed to investigate the predictive role of innate immune cells in CD4+ T cell regulation revealing TLR/NOD pathway activities in monocytes associated with gut‐ and skin‐homing Th2 cells. Thus, this study provides a robust single‐cell reference atlas of healthy children for pediatric research and further demonstrates three applications of the atlas through cellular mapping and identification of gene signatures in the context of FA.