We were able to better characterize ILC precursors (ILCP) and NK cell precursors (NKP) in both mouse and man. Previous studies had suggested that these precursors develop independently, however, using a novel mouse strain with highly sensitive fluorescent reporter that was specifically expressed in ILCP and NKP, we found that these precursor cells were linked in their development and a large fraction of precursor cells in the bone marrow were capable of giving rise to both NK cells and ILCs (Immunity 2019). This work allowed us to redefine the current model for ILC and NK cell development. Moreover, the identification of ILCP/NKP in mice provides the means to better understand the molecular mechanisms that promote functional competence in 'innate' lymphocytes.
The identification of ILCP/NKP in mice also allowed us to compare the process of murine ILC and NK cell development with that operating in humans. In part based on knowledge gleaned by the ILC_REACTIVITY program, we made the first identification and characterization of circulating human ILC precursors (ILCP) that can give rise to human NK cells and ILC subsets in vitro and in vivo (Cell 2017). Remarkably the mouse and human ILCP harbored a similar RNA 'signature' and showed analogous functional properties. This suggests that the process of ILC and NK cell development may be strongly conserved between these two species (Immunity 2018). As such, knowledge derived from mouse studies may have important implications for future human studies aimed at using ILCs in the context of disease.
In another series of experiments, we were able to better understand how ILC function was regulated in the intestine (a critical mucosal barrier) in response to pathogens. In general terms, ILC activation alters several metabolic pathways, that provide 'primed' ILCs with novel functional and migratory attributes. This allows these activated ILCs to contribute more efficiently to immune defense within the tissue (Science 2022).
Using novel imaging approaches and intra-vital microscopy, we have been able to monitor, for the first time, the behavior and dynamics of ILC3 subsets in distinct regions of the intestine, under steady-state as well as inflammatory/infectious conditions (Nature Immunology, 2022). We show that gut ILC3 are immotile under healthy conditions but are shift to patrol barrier sites upon inflammation. We uncovered a role for chemokine in regulating T cell versus ILC3 patrolling. As knowledge in this arena is very limited, these ground-breaking studies help define a working model for the field.
In addition, several important additional studies on human NK cells and ILCs were performed that benefitted from knowledge gleaned by the ILC_REACTIVITY program. These included studies on metabolic changes associated with human NK cell (Blood Adv 2021) and ILC2 (Nature Immunology 2021) homeostasis, growth and activation. Finally, we were able to further delineate signals involved in human ILCP differentiation, especially those involved in the generation of human group 3 ILCs (Nature Communications 2022).
Overall, the main objectives of the ILC_REACTIVITY program were achieved with publication of several high-impact papers that moreover provided novel ways to think about the biology of human and mouse ILC subsets in the context of healthy tissue homeostasis as well as under conditions of inflammation and infection.
