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The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122729/ https://www.ncbi.nlm.nih.gov/pubmed/30180168 http://dx.doi.org/10.1371/journal.pbio.2005046 |
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author | 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 Kelly, Deirdre Lee, Steven P. Parekkadan, Biju Turley, Shannon J. Fletcher, Anne L. |
author_facet | 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 Kelly, Deirdre Lee, Steven P. Parekkadan, Biju Turley, Shannon J. Fletcher, Anne L. |
author_sort | Knoblich, Konstantin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6122729 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61227292018-09-16 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 Kelly, Deirdre Lee, Steven P. Parekkadan, Biju Turley, Shannon J. Fletcher, Anne L. PLoS Biol Short Reports 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. Public Library of Science 2018-09-04 /pmc/articles/PMC6122729/ /pubmed/30180168 http://dx.doi.org/10.1371/journal.pbio.2005046 Text en © 2018 Knoblich et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Short Reports 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 Kelly, Deirdre Lee, Steven P. Parekkadan, Biju Turley, Shannon J. Fletcher, Anne L. The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation |
title | The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation |
title_full | The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation |
title_fullStr | The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation |
title_full_unstemmed | The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation |
title_short | The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation |
title_sort | human lymph node microenvironment unilaterally regulates t-cell activation and differentiation |
topic | Short Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122729/ https://www.ncbi.nlm.nih.gov/pubmed/30180168 http://dx.doi.org/10.1371/journal.pbio.2005046 |
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