3 research outputs found
Human innate lymphoid cell trafficking and function in vivo
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
Microbiological diagnosis of adult tuberculous meningitis in a ten-year cohort in Indonesia
Item does not contain fulltex
Distinct developmental pathways from blood monocytes generate human lung macrophage diversity
The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo