A Phenotypically Distinct Human Th2 Cell Subpopulation Is Associated With Development of Allergic Disorders in Infancy

ABSTRACT Background Little is known about the ontogeny of T cell immunity during infancy in farming and urban lifestyles due to the lack of immunophenotyping in such birth cohorts. Methods Two birth cohorts (farming and urban) at differing risks and rates of allergic diseases were compared. Blood mononuclear cells were collected from infants at birth, and 6 and 12 months of age. Full spectrum flow cytometry, followed by traditional gating and the Scalable Weighted Iterative Flow‐clustering Technique (SWIFT) high‐dimensional analysis, were used to identify cell populations that differed between farming and urban infants. Additionally, single‐cell RNAseq and multiplex cytokine assays were used to assess the function of cell populations of interest. Results Several regulatory T cell (Treg) subpopulations were elevated in farming lifestyles and in non‐atopic infants. A unique effector memory CD25 + CD127 + CD161 − CD49d + CCR4 + CRTH2 + Th2 population was elevated at 6 months in urban infants and in those who developed atopic dermatitis and/or food allergy and allergic sensitization. Although this population shared Th2 and IL‐9 skewing with Th2A cells, the population uniquely failed to express CD161, produced more IL‐2 and TNF‐α, and upregulated the differentially expressed genes (DEGs), FOXP3 and the cytokine inducible SH2‐containing protein gene ( CISH ) relative to Th2A cells. This population has been termed Th2B cells. Conclusion We describe a unique effector memory Th2 population elevated in urban high‐risk infants, potentially implicated in the development of allergic disease.