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

Autor: Konstantin Knoblich, Sara Cruz Migoni, Susan M Siew, Elizabeth Jinks, Baksho Kaul, Hannah C Jeffery, Alfie T Baker, Muath Suliman, Katerina Vrzalikova, Hisham Mehenna, Paul G Murray, Francesca Barone, Ye H Oo, Philip N Newsome, Gideon Hirschfield, Deirdre Kelly, Steven P Lee, Biju Parekkadan, Shannon J Turley, Anne L Fletcher
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: PLoS Biology, Vol 16, Iss 9, p e2005046 (2018)
Druh dokumentu: article
ISSN: 1544-9173
1545-7885
DOI: 10.1371/journal.pbio.2005046
Popis: 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.
Databáze: Directory of Open Access Journals
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