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PLoS Biol. 2018 Sep 4;16(9):e2005046. doi: 10.1371/journal.pbio.2005046. eCollection 2018 Sep.

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

Author information

1
Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
2
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
3
Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
4
Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom.
5
Department of Gastroenterology and James Fairfax Institute of Paediatric Nutrition, The Children's Hospital at Westmead, Sydney, Australia.
6
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
7
Institute of Head and Neck Studies and Education, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
8
Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
9
National Institute for Health Research Liver Biomedical Research Unit at University Hospitals Birmingham National Health Service Foundation Trust and the University of Birmingham, Edgbaston, Birmingham, United Kingdom.
10
Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.
11
Department of Cancer Immunology, Genentech, South San Francisco, United States of America.

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.

PMID:
30180168
PMCID:
PMC6122729
DOI:
10.1371/journal.pbio.2005046
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

I have read the journal's policy, and the authors of this manuscript have the following competing interests: S. P. Lee is listed as an inventor on the following patent application/patent families regarding development of CLEC14A CAR T cells: PCT/GB2010/001689 (published as WO2011/027132), PCT/GB2016/050134 (published as WO2016/116760), PCT/GB2017/050686, and PCT/GB2017/050689.

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