Human innate lymphoid cell trafficking and function in vivo

Abstract

Human organs and tissues, such as the lung, are composed of various spatially distinct anatomical compartments. Each compartment represents a different tissue environment within the organ, performs specific functions and in turn promotes the development, migration, and function of specific cell types. Innate lymphoid cells (ILCs) are innate immune cells that perform important functions as one of the first responders in immune defense and as maintainers of tissue homeostasis. ILCs are often considered as the innate counterpart of T cells, but instead on specific antigens, ILCs heavily rely on environmental signals for their development, activation, and function. Therefore, investigating the migration and spatial distribution of human ILC subsets between compartments and how it relates to their function is important. In the past several years this has been studied in both mice and humans, but human studies have been more difficult due to experimental limitations. To overcome this limitation and fully investigate human ILC trafficking and function in vivo, we used the MISTRG humanized mouse model in combination with intravascular cell labeling to assess human ILCs in the vascular and tissue compartments. Additional methods were employed to further investigate specific questions, for example the OP9-DL1 co-culture system to assess the differentiation potential of specific ILC subsets and single-cell RNA-sequencing to investigate ILC heterogeneity between anatomical compartments.

In Paper I, we identified a specific population of human CD5+ ILCs that resides in the vascular compartment of the lungs and various organs. These CD5+ ILCs are comprised of mature ILC1s and an immature population that can differentiate into mature ILCs. CD5+ ILCs may function as sentinels that patrol the blood vessels and are recruited into the tissue during inflammation. In Paper II, we investigated the relationship between human ILC localization and proliferation. We identified a specific proliferative ILC population expressing the transcription factor TCF-1 that resided predominantly in the spleen and the vasculature of nonlymphoid organs. In Paper III, we investigated the heterogeneity of human ILCs and NK cells in the vascular and tissue compartment of the lungs. We found that ILC subsets are heterogenous and distributed in both vascular and tissue compartments. In contrast, NK cell subsets were strictly divided between CD56dim subsets in the vasculature and CD56bright and transitional subsets in the tissue. Furthermore, the spatial distribution of ILCs and NK cell subsets was linked to biological functions, such as migration, tissue residency, and adaptation to the tissue microenvironment.

Overall, this thesis provides new insights into human ILCs, specifically how their features and functions are regulated by their localization and the tissue microenvironment. These insights further our understanding of human ILC biology, and potentially contribute to the development of new treatments for human disease by modulating ILC migration.