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

Research output: Contribution to journalArticle

External organisations

  • Rutgers University
  • Genentech, S. San Francisco, California, USA.
  • Birmingham QEH

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 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.

Details

Original languageEnglish
JournalPLoS Biology
Publication statusPublished - 4 Sep 2018