Project Summary
The Type 3 cytokine (IL-17 and IL-22) producing lymphocytes (T3L) are strategically located at the
mucocutaneous barrier tissues and serve as sentinels of tissue perturbations at the interface with the
outside world. Skin resident T3L develop in early life and perform dual function: Early life, they promote
tissue fitness by interacting with commensals to produce tonic IL-17; and throughout life, they defend
against pathogens by rapid secretion of IL-17 essential for recruitment of neutrophils to inflamed tissues
and fortifying the barrier tissues. Commensal dysbiosis by low dose antibiotics during early life of
animals (E15 for mice and 24-28 weeks of gestation in humans) can lead to aberrant IL-17 production and
is linked to metabolic dysfunctions observed in adults, including obesity. We discovered recently that a
subset of T3L in mice can sense the dietary cholesterol metabolites oxysterols to calibrate their function.
These cells arise immediately after birth in mice and they are the fastest (innate-like) lymphoid
responders to tissue perturbations. The recognition of oxysterols by T3L is mediated by the G protein-
coupled receptor GPR183, which is expressed by all T3L in mice and humans. Gpr183 has been
genetically linked to psoriasis, colitis and Type 1 diabetes susceptibility in humans. In mice, early life
skin T3L subset mediates IL-17-driven psoriatic responses downstream of Toll-like Receptor signaling in
keratinocytes. This function is diet-modulated and dependent on GPR183, with high cholesterol diet
leading to severe diseases, and conversely, vegetarian diet dampening IL-17 production and dramatically
moderating disease severity. This discovery is the first to identify potential sensors of immune
modulatory dietary metabolites on lymphocytes outside the gut. In humans T3L are known to be
important in psoriasis in adults, but almost nothing is known about them in early life immune system.
This gap in knowledge in large part exists because there is no systematic census of T3L and their
interacting partners in mucocutaneous tissues of children. This proposal will fill this gap using innovative,
unbiased, complementary single cell interrogation methods to catalogue all immune cell types and states
in the skin of children from infancy to adulthood, stratified multi-parametrically, including BMI, dietary
habits and infection history. The skin cell atlas of children will be instrumental in establishing correlation
between dietary habits and propensity towards hyper inflammatory responses, modulated by skin-resident
T3L. The genome-wide information rich map will identify gene networks that govern intercellular
communications and cell lineage diversification, setting a major precedent of tissue immune systems
relevant for childhood immunity, and accelerate progress towards defining mechanisms of early life
immune system development.
