Type 3 innate lymphoid cells (ILC3) perform multiple functions in host physiology. However, most of these functions have been elucidated in the context of T cell depletion. There is an extensive overlap of regulatory and functional networks between ILC3 and Th17 cells and how these two cell types contribute to immunity is unclear. Identification of non-redundant functions of ILC3 has been impeded by the lack of ILC3 depletion models that preserve normal T cell development and differentiation. To address this gap in knowledge, we created the first model in which ILC3 development is prevented, but B and T cell development and T cell differentiation is normal. Using this model we demonstrate a non-redundant function of ILC3 in mucosal protection against an intestinal pathogen. We will examine the specific mechanism of this protection, as well as identify novel T cell-independent functions of ILC3. Moreover, we will uncouple the role of LTi in lymph node and Peyer?s patch development from the role of adult lamina propria ILC3. We will also investigate the role of ILC3 in regulating homeostasis with the intestinal microbiota. Overall, our studies will elucidate the cellular and molecular mechanisms controlling non-redundant ILC3 functions in both maintaining a healthy gut and regulating infectious intestinal inflammation. We expect the results to lead to the development of more specific strategies for targeting ILC3 and Th17 cells to improve intestinal immune dysbalance or prevent pathologic intestinal inflammation.
ILC3 and Th17 cells provide important protection at barrier surfaces, however the non-redundant functions of these two cell types has been difficult to determine. We generate a novel genetic model for specific depletion of ILC3, but normal T cell development and differentiation and discovered a non-redundant function for ILC3 in mucosal defense. We will use this model to further examine the mechanisms of ILC3- mdeiated protection in lymphocyte-replete mice.