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The Origin and Molecular Identity of Immune-Interacting Reticular Cells in Secondary Lymphoid Organs


Lütge, Mechthild. The Origin and Molecular Identity of Immune-Interacting Reticular Cells in Secondary Lymphoid Organs. 2024, University of Zurich, Faculty of Science.

Abstract

Innate and adaptive immune responses are induced and controlled in secondary lymphoid organs (SLOs), including lymph nodes, splenic white pulp, and Peyer's patches. Each SLO monitors specific body regions and fluids and is underpinned by specialized fibroblastic reticular cells (FRCs) that form dedicated niches to coordinate immune responses. FRCs have multiple core functions that are critical to decide about the strength and specificity of immune responses. They form a fibrous network as the structural foundation of SLOs, establish chemokine gradients that direct the coordinated movement of immune cells, and provide growth and activation factors to ensure immune cell homeostasis and activation. Because of their critical role in efficient immune regulation, understanding the biology of FRCs can guide meaningful research on therapeutic manipulation of innate and adaptive immune processes. However, while FRCs have been extensively studied in individual murine SLOs, less is known about FRCs in human lymphoid organs. Furthermore, the extent to which FRC-supported niches are mirrored across SLOs remains unknown, limiting our understanding of the induction and maintenance of systemic immunity. In the studies included in this thesis, we combined high- resolution transcriptomic analysis with state-of-the-art tools to dissect the molecular phenotypes and tissue context of FRCs across SLOs and species under homeostatic and inflammatory conditions.

Our analysis revealed that across SLOs, shared FRC subsets in the B cell zone use canonical signals to engage in bidirectional crosstalk with circulating immune cells. The identified interaction circuits are conserved across murine and human SLOs, where they maintain FRC niches and ensure efficient humoral immune responses. In-depth analysis of human lymph node FRCs further revealed specialized FRC subsets and vascular smooth muscle cells that share molecular programs to form the perivascular niche and support the extensive vasculature in human lymph nodes. Analysis of clinically inflamed lymph nodes further identified peptidase inhibitor 16 (PI16)-expressing reticular cells (PI16+ RCs) as a highly reactive FRC subset in the perivascular niche. Upon inflammatory activation, PI16+ RCs in the subcapsular sinus engage in a bidirectional crosstalk with macrophages, suggesting that PI16+ RCs form a highly reactive macrophage niche in human lymph nodes.

In summary, our studies reveal a feedforward paradigm in which circulating immune cells can utilize canonical interaction circuits to efficiently engage FRC-supported niches. The identified interaction circuits are conserved across human and mouse SLOs. Together with our detailed analysis of the human lymph node FRC landscape, these findings can guide future research to understand and target immune cell niches across species.

Abstract

Innate and adaptive immune responses are induced and controlled in secondary lymphoid organs (SLOs), including lymph nodes, splenic white pulp, and Peyer's patches. Each SLO monitors specific body regions and fluids and is underpinned by specialized fibroblastic reticular cells (FRCs) that form dedicated niches to coordinate immune responses. FRCs have multiple core functions that are critical to decide about the strength and specificity of immune responses. They form a fibrous network as the structural foundation of SLOs, establish chemokine gradients that direct the coordinated movement of immune cells, and provide growth and activation factors to ensure immune cell homeostasis and activation. Because of their critical role in efficient immune regulation, understanding the biology of FRCs can guide meaningful research on therapeutic manipulation of innate and adaptive immune processes. However, while FRCs have been extensively studied in individual murine SLOs, less is known about FRCs in human lymphoid organs. Furthermore, the extent to which FRC-supported niches are mirrored across SLOs remains unknown, limiting our understanding of the induction and maintenance of systemic immunity. In the studies included in this thesis, we combined high- resolution transcriptomic analysis with state-of-the-art tools to dissect the molecular phenotypes and tissue context of FRCs across SLOs and species under homeostatic and inflammatory conditions.

Our analysis revealed that across SLOs, shared FRC subsets in the B cell zone use canonical signals to engage in bidirectional crosstalk with circulating immune cells. The identified interaction circuits are conserved across murine and human SLOs, where they maintain FRC niches and ensure efficient humoral immune responses. In-depth analysis of human lymph node FRCs further revealed specialized FRC subsets and vascular smooth muscle cells that share molecular programs to form the perivascular niche and support the extensive vasculature in human lymph nodes. Analysis of clinically inflamed lymph nodes further identified peptidase inhibitor 16 (PI16)-expressing reticular cells (PI16+ RCs) as a highly reactive FRC subset in the perivascular niche. Upon inflammatory activation, PI16+ RCs in the subcapsular sinus engage in a bidirectional crosstalk with macrophages, suggesting that PI16+ RCs form a highly reactive macrophage niche in human lymph nodes.

In summary, our studies reveal a feedforward paradigm in which circulating immune cells can utilize canonical interaction circuits to efficiently engage FRC-supported niches. The identified interaction circuits are conserved across human and mouse SLOs. Together with our detailed analysis of the human lymph node FRC landscape, these findings can guide future research to understand and target immune cell niches across species.

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Additional indexing

Item Type:Dissertation (cumulative)
Referees:Ludewig Burkhard, Robinson Mark D., van den Broek Maries
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
UZH Dissertations
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Language:English
Place of Publication:Zürich
Date:14 May 2024
Deposited On:14 May 2024 12:30
Last Modified:15 May 2024 03:38
Number of Pages:203
OA Status:Closed