Exploring a New Immunological Niche: How Fibroblastic Reticular Cells Tune T Cell Immunity Through Notch Signals
Perkey, Eric
2022
Abstract
Notch is an evolutionarily conserved cell-to-cell signaling pathway with important roles throughout biology that has emerged as a critical regulator of mature T cell responses. Pharmacological Notch inhibition is a promising candidate strategy to prevent T cell pathogenicity in graft-versus-host disease (GVHD), the limiting complication of allogeneic bone marrow transplantation (allo-BMT). We found that presentation of the critical Delta-like Notch ligands to T cells is restricted to a cellular niche of non-hematopoietic fibroblastic reticular cells (FRCs) in secondary lymphoid organs. Still, little is known about the nature and regulation of the FRC niche during allo-BMT. Beyond allo-BMT, it is unclear whether T cells receive Notch ligands from the FRC niche or alternative sources, such as professional antigen-presenting cells (APCs). In this thesis, I explored how the FRC niche regulates T cell responses through Notch signaling, both during allo-BMT and in other immunological contexts. First, I uncovered a novel indicator of Notch signaling in activated T cells based on core-2 O-glycosylation of CD43. Using this indicator, I observed that the FRC niche remains the critical source of Notch signals that drive T cell pathology after allotransplantation with reduced intensity or no myeloablative conditioning, contexts in which recipient hematopoietic cells are not profoundly depleted. Next, I documented the role of FRC niches in priming a pathogenic gut-homing program in alloreactive T cells. Inhibiting Notch signals in T cells or eliminating Delta-like ligands in FRCs preferentially prevented the accumulation of effector T cells in the intestines while accumulation of T regulatory cells was relatively preserved. Notch signals were required for the acquisition of the gut-tropic α4β7 integrin in effector, but not regulatory T cells. These findings provide possible mechanistic explanations for the role of Notch in gastrointestinal GVHD. Next, we explored how allo-BMT regulates the FRC niche. Allo-BMT enhanced inflammatory gene programs in FRCs, including upregulation of Delta-like4 and antigen-presentation machinery. Delta-like4 upregulation was restricted to a subset of CD157hi FRCs and depended on signals from alloantigen-activated T cells, suggesting that early crosstalk between T cells and FRC subsets establishes a pathogenic niche that drives GVHD. We then investigated whether FRCs could present MHC class II-restricted alloantigens in a CD4+ T cell-driven model of GVHD. While FRCs were necessary to drive GVHD through the provision of Notch ligands, they were dispensable sources of alloantigens, suggesting that T cell activation requires distinct physical interaction with APCs and FRCs. We tested this model using dendritic cell (DC) immunization to control the source of antigen. Even when we immunized recipients with Delta-like4hi DCs, FRCs acted non-redundantly to drive Notch-dependent differentiation of CD8+ T cells into KLRG1hi short-lived effector cells, suggesting that FRCs deliver Notch signals to T cells independently of antigen. We next studied the effects of Notch signaling in naïve T cells. Transcriptomic profiling revealed Notch-dependent regulation of naïve T cells, with FRCs as the source of Notch ligands. Collectively, these studies document the non-redundant role of the FRC niche in controlling Notch-dependent T cell activation and differentiation. We propose that the availability of Notch ligands in the FRC niche is dynamically regulated to control effector T cell responses during allo-BMT and potentially other immune responses. Further understanding T cell-FRC interactions will suggest novel therapies to dampen pathogenic or amplify protective immunity.Deep Blue DOI
Subjects
T cells Fibroblastic reticular cells Graft-versus-host disease Notch signaling
Types
Thesis
Metadata
Show full item recordCollections
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.