Notch in the Niche: How Stromal Notch Ligands Regulate T Cell Development and Differentiation in Secondary Lymphoid Tissues / Ashley Nicole Vanderbeck.

Format:

Book

Thesis/Dissertation

Author/Creator:

Vanderbeck, Ashley Nicole, author.

Contributor:

University of Pennsylvania. Immunology, degree granting institution.

Language:

English

Subjects (All):

Immunology.

Cellular biology.

Molecular biology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Local Subjects:

Immunology.

Cellular biology.

Molecular biology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Physical Description:

1 online resource (106 pages)

Distribution:

Ann Arbor : ProQuest Dissertations & Theses, 2023

Contained In:

Dissertations Abstracts International 85-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Language Note:

English

Summary:

Notch signaling is an evolutionarily conserved cell-to-cell signaling pathway that regulates cellular differentiation and function across multiple tissue types. The Notch pathway operates through direct cellular interactions within specialized niches where signal-sending cells present Notch ligands and signal-receiving cells express Notch receptors. Delivery of Notch signals can modulate cell fate decisions, including lineage commitment and cellular function. In this study, we examined the role of Notch signaling within secondary lymphoid organ niches in the context of extrathymic T-cell development and mature T-cell function. Although T-cell development is normally restricted to the thymus, extrathymic T-cell development in secondary lymphoid organs such as mesenteric lymph nodes (MLN) arises in athymic mice as well as during times of thymopoietic stress such as post-bone marrow transplantation (BMT). A population of T-cell progenitors can be found in the MLN of 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 ligands throughout the process, remains unknown. We found that, as for thymocyte development, Notch ligand Dll4 played an essential role in generation of early T-cell progenitors found in the MLN. The source of Dll4 resided within subsets of non-hematopoietic fibroblastic reticular cells (FRC) lineage traced by a Ccl19-Cre transgene. We also identified Ccl19-Cre+ FRC as essential regulators of allogeneic T-cell pathogenicity in gastrointestinal Graft-Versus-Host-Disease (GVHD), a life-threatening complication of allogeneic BMT. Dll4 expression in Ccl19-Cre+ FRC was critical for upregulation of the gut-homing integrin, α4β7. Notch-deprivation reduced surface α4β7 and trafficking of alloreactive T-cells to the GI-tract. Notch inhibition did not transcriptionally regulate α4 orβ7, but instead skewed the surface integrin repertoire to favor α4β1 via increased competition between β1 and β7 for α4 binding. Our data shed light on new roles for Dll4-mediated Notch signaling in secondary lymphoid organs during regulation extrathymic T-cell development and alloreactive T-cell pathogenicity.

Notes:

Source: Dissertations Abstracts International, Volume: 85-08, Section: B.

Advisors: Laufer, Terri; Maillard, Ivan P.; Committee members: Bailis, Will; Vahedi, Golnaz; Pear, Warren.

Department: Immunology.

Ph.D. University of Pennsylvania 2023.

Local Notes:

School code: 0175

ISBN:

9798381471670

Access Restriction:

Restricted for use by site license.