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The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation.
- Source :
- PLoS Biology; 9/4/2018, Vol. 16 Issue 9, p1-24, 24p, 5 Graphs
- Publication Year :
- 2018
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- T cells
LYMPH nodes
PHENOTYPES
PROSTAGLANDINS
ADENOSINES
Subjects
Details
- Language :
- English
- ISSN :
- 15449173
- Volume :
- 16
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- PLoS Biology
- Publication Type :
- Academic Journal
- Accession number :
- 131582304
- Full Text :
- https://doi.org/10.1371/journal.pbio.2005046