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

Konstantin Knoblich, Sara Cruz Migoni, Susan Siew, Elizabeth Jinks, Baksho Kaul, Hannah Jeffery, Alfie Baker, Muath Suliman, Katerina Vrzalikova, Hisham Mehanna, Paul Murray, Francesca Barone, Philip Newsome, Gideon Hirschfield, Deirdre Kelly, Ye Htun Oo, Steven Lee, Biju Parekkadan, Shannon Turley, Anne Fletcher

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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 four 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 TGFRI. Each mechanistic pathway was druggable, and a cocktail of inhibitors, targeting all four mechanisms, entirely reversed the suppressive effect of FRCs. T cells were not permanently anergized 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 four-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 four feasible strategies, used alone or in combinations, to boost primary T cell responses to infection or cancer by pharmacologically targeting FRCs.
Original languageEnglish
Article numbere2005046
Number of pages24
JournalPLoS Biology
Volume16
Issue number9
DOIs
Publication statusPublished - 4 Sep 2018

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