Regulatory roles of type-2 lymphocytes on local fibroblast biology in health and disease.

Fibroblasts are critical for organ homeostasis and tissue-repair, but also contribute to fibrosis in serious diseases. Immune cells regulate fibroblast function, although the complex tissue- temporal- and disease-specific features of such interactions have made therapeutic targeting difficult. We found that tissue-resident type-2 lymphocytes control novel fibroblast-progenitor niches in solid organs. Hence, we hypothesize that type-2 lymphocytes orchestrate local fibroblast homeostasis and guide their biology throughout tissue-regeneration, while perturbations of this axis underpin fibrosis. Using cutting-edge single-cell and spatial techniques we will reveal the cellular and molecular makeup of specific immune-fibroblast niches in organs, and importantly, discover how these different cells interact dynamically. We will then use advanced 3D cell-cultures that model the complex organ environment, and refined mouse models of both tissue-repair and tissue-fibrosis to determine how specific lymphocytes locally control fibroblast function. We will simultaneously define this novel immune-fibroblast progenitor niche in human organs using highly-multiplexed spatial and single-cell approaches; conserved mechanisms will be identified and developed as therapeutic targets. We will focus on the pancreas and lung, where a better understanding of tissue-regeneration post injury (i.e. acute pancreatitis, viral infection, allergens or toxins) or mechanisms of fibrosis (i.e. chronic pancreatitis, lung fibrosis) will address major global health challenges.