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

Knoblich, Konstantin, Cruz Migoni, Sara, Siew, Susan M, Jinks, Elizabeth, Kaul, Baksho, Jeffery, Hannah C, Baker, Alfie T, Suliman, Muath, Vrzalikova, Katerina, Mehenna, Hisham, Murray, Paul G, Barone, Francesca, Oo, Ye H, Newsome, Philip N, Hirschfield, Gideon M, Kelly, Deirdre, Lee, Steven P, Parekkadan, Biju, 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

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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
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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

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