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

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The human lymph node microenvironment unilaterally regulates T cell activation and differentiation. / Knoblich, Konstantin; Cruz Migoni, Sara; Siew, Susan; Jinks, Elizabeth; Kaul, Baksho; Jeffery, Hannah; Baker, Alfie; Suliman, Muath; Vrzalikova, Katerina; Mehanna, Hisham; Murray, Paul; Barone, Francesca; Newsome, Philip; Hirschfield, Gideon; Kelly, Deirdre; Oo, Ye Htun; Lee, Steven; Parekkadan, Biju; Turley, Shannon; Fletcher, Anne.

In: PLoS Biology, 04.09.2018.

Research output: Contribution to journalArticlepeer-review

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@article{3023445ed2ac4288a9b96b32b38f7a2c,
title = "The human lymph node microenvironment unilaterally regulates T cell activation and differentiation",
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 na{\"i}ve 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.",
author = "Konstantin Knoblich and {Cruz Migoni}, Sara and Susan Siew and Elizabeth Jinks and Baksho Kaul and Hannah Jeffery and Alfie Baker and Muath Suliman and Katerina Vrzalikova and Hisham Mehanna and Paul Murray and Francesca Barone and Philip Newsome and Gideon Hirschfield and Deirdre Kelly and Oo, {Ye Htun} and Steven Lee and Biju Parekkadan and Shannon Turley and Anne Fletcher",
year = "2018",
month = sep,
day = "4",
doi = "10.1371/journal.pbio.2005046",
language = "English",
journal = "PLoS Biol.",
issn = "1544-9173",
publisher = "Public Library of Science (PLOS)",

}

RIS

TY - JOUR

T1 - The human lymph node microenvironment unilaterally regulates T cell activation and differentiation

AU - Knoblich, Konstantin

AU - Cruz Migoni, Sara

AU - Siew, Susan

AU - Jinks, Elizabeth

AU - Kaul, Baksho

AU - Jeffery, Hannah

AU - Baker, Alfie

AU - Suliman, Muath

AU - Vrzalikova, Katerina

AU - Mehanna, Hisham

AU - Murray, Paul

AU - Barone, Francesca

AU - Newsome, Philip

AU - Hirschfield, Gideon

AU - Kelly, Deirdre

AU - Oo, Ye Htun

AU - Lee, Steven

AU - Parekkadan, Biju

AU - Turley, Shannon

AU - Fletcher, Anne

PY - 2018/9/4

Y1 - 2018/9/4

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pbio.2005046

DO - 10.1371/journal.pbio.2005046

M3 - Article

JO - PLoS Biol.

JF - PLoS Biol.

SN - 1544-9173

ER -