Every year, immune-related disorders affect millions of children worldwide. The fetal immune system during pregnancy plays a central role in determining the child’s future health. In particular, immune cells that secrete IL-17 promote tissue development and homeostasis, and serve as sentinels for the detection of microbes. For example, murine IL-17 dysregulation due to microbiota disruption after antibiotics administration is linked to obesity later in life, and increased amounts of IL-17 in pregnancy cause behavioral abnormalities, reminiscent of autism spectrum disorder. Therefore, a better understanding of the origin and development of immune cells with the ability to mediate immune effector functions in fetal life has important clinical implications, especially in providing novel insights into how child-specific diseases arise. This proposal focuses on the developmental origin of fetal-derived murine and human IL-17 producing T cell subsets.

We plan to identify and characterize the murine embryonic progenitors of IL-17 producing gd T cell (Tgd17), exploiting our recent discovery of a network of transcription factors (TFs) that shape the identity of Tgd17 cells. The progenitor subsets will be identified in hematopoietic organs of the fetus using fluorescent reporters for the TFs, analyzed at a single cell level, and transplanted into animals to determine their generative potential. In parallel, we will study the human Tgd17 progenitor counterpart from umbilical cord blood. We will test culture conditions that support and expand progenitors that preferentially give rise to human Tgd17 cells. A detailed phenotypical and transcriptional analyses of the in vitro generated and ex vivo isolated subsets will be performed.

Dissecting the molecular requirements for Tgd17 cells development has critical clinical implications, as early immune events during the fetal stage will shape the immune status during childhood and adult life.