ArticlePLoS biology2018
The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation.
Article in PLoS biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 3 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
67 citing papers in PubMed, 3 syntheses or guidelines pooled it, 103 citations in OpenAlex.
- The clinical importance of the host anti-tumour reaction patterns in regional tumour draining lymph nodes in patients with locally advanced resectable gastric cancer: a systematic review and meta-analysis.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2023Pooled it
- Modeling Immunity In Vitro: Slices, Chips, and Engineered Tissues.Annual review of biomedical engineering · 2021Pooled it
- LN-Derived Fibroblastic Reticular Cells and Their Impact on T Cell Response-A Systematic Review.Cells · 2021Pooled it
- Lymph node extracellular matrix skews the immune function of human fibroblastic reticular cells.iScience · 2026Article
- Topological analysis of the human lymph node reticular network predicts outcome in breast cancer.The Journal of pathology · 2026Article
- Engineered macroporous gelatin scaffolds enhance lymph node fibroblastic reticular cell identity and enable diabetogenic T cell immunomodulation.Biomaterials · 2026Article
- Immunometabolic Reprogramming of Fibroblastic Reticular Cells in the Tumor Immune Microenvironment.BioMed research international · 2026Review
- IL7-TBRII, a Dual Cytokine Modulator Targeting IL-7 and TGF-β Pathways, Inhibits Tumor Progression and Metastasis.Immune network · 2025Article
- Bioengineering and omics approaches for Type 1 diabetes practical research: advancements and constraints.Annals of medicine · 2025Review
- Decellularized lymph node sections with preserved extracellular matrix for stromal cell culture.Scientific reports · 2025Article
- Paracrine regulations of IFN-γ secreting CD4Matrix biology : journal of the International Society for Matrix Biology · 2025Article
- Ex vivo model of functioning human lymph node reveals role for innate lymphocytes and stroma in response to vaccine adjuvant.Cell reports · 2025Article
- Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies.Molecular cancer · 2025Review
- Splenic fibroblastic reticular cells orchestrate dendritic cell maturation and facilitate CD8Science advances · 2025Article
- Fibroblastic reticular cells form reactive myeloid cell niches in human lymph nodes.Science immunology · 2025Article
- CXCL12+ fibroblastic reticular cells in lymph nodes facilitate immune tolerance by regulating T cell-mediated alloimmunity.The Journal of clinical investigation · 2025Article
- Functional organotypic human lymph node model with native immune cells benefits from fibroblastic reticular cell enrichment.Scientific reports · 2025Article
- Deciphering the Human Germinal Center: A Review of Models to Study T-B Cell Interactions.European journal of immunology · 2025Review
- Lymph nodes as gatekeepers of autoimmune diseases.RMD open · 2024Review
- Human lymph node fibroblastic reticular cells maintain heterogeneous characteristics in culture.iScience · 2024Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
20 authors at 4 institutions in 3 countries.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.