The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation.

Knoblich, Konstantin and Cruz Migoni, Sara and Siew, Susan M and Jinks, Elizabeth and Kaul, Baksho and Jeffery, Hannah C and Baker, Alfie T and Suliman, Muath and Vrzalikova, Katerina and Mehenna, Hisham and Murray, Paul G and Barone, Francesca and Oo, Ye H and Newsome, Philip N and Hirschfield, Gideon M and Kelly, Deirdre and Lee, Steven P and Parekkadan, Biju and Turley, Shannon J and Fletcher, Anne L (2018) The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation. PLoS biology, 16 (9). e2005046. ISSN 1545-7885. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

[img]
Preview
Text (PDF file format)
The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation.pdf - Published Version
Available under License Creative Commons Attribution 4.0.

Download (5MB) | Preview
Official URL: https://journals.plos.org/plosbiology/article?id=1...

Abstract

The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regulatory checkpoint in human peripheral T-cell activation through 4 mechanisms simultaneously utilised. Human tonsil and lymph node-derived FRCs constrained the proliferation of both naïve and pre-activated T cells, skewing their differentiation away from a central memory T-cell phenotype. FRCs acted unilaterally without requiring T-cell feedback, imposing suppression via indoleamine-2,3-dioxygenase, adenosine 2A Receptor, prostaglandin E2, and transforming growth factor beta receptor (TGFβR). Each mechanistic pathway was druggable, and a cocktail of inhibitors, targeting all 4 mechanisms, entirely reversed the suppressive effect of FRCs. T cells were not permanently anergised by FRCs, and studies using chimeric antigen receptor (CAR) T cells showed that immunotherapeutic T cells retained effector functions in the presence of FRCs. Since mice were not suitable as a proof-of-concept model, we instead developed a novel human tissue-based in situ assay. Human T cells stimulated using standard methods within fresh tonsil slices did not proliferate except in the presence of inhibitors described above. Collectively, we define a 4-part molecular mechanism by which FRCs regulate the T-cell response to strongly activating events in secondary lymphoid organs while permitting activated and CAR T cells to utilise effector functions. Our results define 4 feasible strategies, used alone or in combinations, to boost primary T-cell responses to infection or cancer by pharmacologically targeting FRCs.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: QW Microbiology. Immunology
Divisions: Planned IP Care > Gastroentrology
Related URLs:
Depositing User: Mrs Semanti Chakraborty
Date Deposited: 19 Jul 2019 10:36
Last Modified: 19 Jul 2019 10:36
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2242

Actions (login required)

View Item View Item