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3276 Fibroblastic Stromal Cells Expressing Delta-like Notch Ligands Control Extrathymic T Cell Development in Mesenteric Lymph Nodes

Program: Oral and Poster Abstracts
Session: 701. Experimental Transplantation: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, hematopoiesis, immunology, Biological Processes, Technology and Procedures
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Ashley Vanderbeck1*, Samantha Kelly, BS2*, Leolene Carrington, PhD3*, Eric Perkey, MD, PhD3*, Anneka Allman, BA4*, Frederick Allen, PhD5*, Joshua D Brandstadter, MD, PhD, MSc6, Burkhard Ludewig, PhD7* and Chris Siebel, PhD, BA8*

1University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA
2Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
3University of Pennsylvania, Philadelphia, PA
4Department of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA
5Perelman School of Medicine, Philadelphia, PA
6Division of Hematology and Oncology, Abramson Cancer Center University of Pennsylvania, SWARTHMORE, PA
7Institute of Immunobiology, Kantonsspital St. Gallen, St Gallen, Switzerland
8Department of Oncology, Genentech Inc, South San Francisco, CA

Early T cell development is supported by signals mediated by the Notch1 receptor in T lineage progenitors and Delta-like4 (Dll4) ligand in thymic epithelial cells. Although T cell development is normally restricted to the thymus, extrathymic T cell development has been reported in athymic Foxn1nu/nu nude mice as well as during times of thymopoietic stress such as post-bone marrow transplantation (BMT). A population of CD4+CD8a double positive T cell progenitors can be found in the mesenteric lymph nodes (MLN) in both athymic mice and early post-BMT, suggesting the presence of an extrathymic niche conducive to T cell development. However, whether Notch signaling is required, as well as the cellular source(s) of Notch ligand throughout the process in the MLN, remains unknown. We hypothesize that MLNs harbor a unique environment in which Notch ligands are available to circulating progenitors and critical to sustain extrathymic T cell development in these contexts. To test this, we utilized systemic neutralizing antibodies as well as loss-of-function genetic models to assess whether the Notch ligands Dll4 or Dll1 are important for extrathymic T cell development. We found that, like homeostatic thymocyte development, Dll4 appears to play an essential role in generation of early T cell progenitors found in the MLN. Furthermore, the source of Dll4 appears to reside within subsets of non-hematopoietic fibroblastic stromal cells lineage traced by a Ccl19-Cre transgene. In sum, these findings shed new light on the cellular and molecular cues regulating T cell development outside of the thymus.

Disclosures: Brandstadter: EUSA Pharma: Consultancy.

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*signifies non-member of ASH