Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - ILC_REACTIVITY (Biological Determinants of ILC Reactivity for Immune Responses in Health and Disease)

Teaser

Innate lymphoid cells (ILC) are a newly described family of blood cells that contribute to the first-line immune defense against viral, bacterial, and parasitic infections. Several distinct ILC subsets (ILC1, ILC2, ILC3) have been described that are active during both fetal...

Summary

Innate lymphoid cells (ILC) are a newly described family of blood cells that contribute to the first-line immune defense against viral, bacterial, and parasitic infections. Several distinct ILC subsets (ILC1, ILC2, ILC3) have been described that are active during both fetal and adult life and play important roles in tissue homeostasis. ILCs resemble previously described natural killer (NK) cells; both cell types possess a \'natural\' effector function which is immediately available during immune responses. In contrast, T cells and B cells that provide immune ‘memory’ after infection or vaccination (‘adaptive’ immunity) require days or weeks in order to respond. This dichotomy in the timing of ‘innate’ and ‘adaptive’ immunity has important implications as it allows the organism to maintain immune defense rapidly and for long periods of time. Still, how NK cells and ILCs acquire the capacity for rapid responses and how these diverse cell types are integrated into the complex coordination of immunity remains unclear.

The ILC_REACTIVITY proposal investigates the critical control points that can regulate ILC and NK cell function during immune responses. Using a combination of cutting-edge technologies, the signals that control various aspects of ILC and NK cell ‘lifestyle’ (their generation, survival, proliferation, activation and death) will be uncovered and deciphered. Together, these complementary studies have already shed new light on the biological determinants which regulate ILC reactivity. For example, the growth factors that are important for generation of ILCs in bone marrow have been identified, that may help to design ways to grow human ILCs for cellular therapies. Understanding how ILC responsiveness is controlled prior to and during immune responses may have important implications for disease intervention, for example in the context of infection or cancer.

Work performed

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. 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. We had previously described a novel circulating human ILCP; 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. 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.

Final results

Using novel imaging approaches and intra-vital microscopy, we have been able to set up conditions that allow us monitor the real-time behavior and dynamics of ILC subsets in distinct regions of the intestine, under steady-state as well as inflammatory/infectious conditions. As knowledge in this arena is very limited, we are expecting that these ground-breaking studies will define a working model for the field.

Website & more info

More info: https://research.pasteur.fr/fr/team/innate-immunity/.