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

Konstantin Knoblich1,2, Sara Cruz Migoni1, Susan M Siew3,4,5

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Human fibroblastic reticular cells (FRCs) suppress T-cell activation via four molecular mechanisms. Targeting these pathways can enhance T-cell responses for immunotherapy and infection treatment.

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Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • The lymphoid organ microenvironment supports immune function.
  • Fibroblastic reticular cells (FRCs) are crucial for T-cell support in mouse lymph nodes.
  • Human FRCs' role in T-cell regulation is largely uncharacterized.

Purpose of the Study:

  • To investigate the mechanisms by which human FRCs regulate T-cell activation.
  • To determine if FRC-mediated suppression can be overcome pharmacologically.
  • To assess the impact of FRCs on T-cell function in the context of immunotherapy.

Main Methods:

  • Human tonsil and lymph node FRCs were isolated and co-cultured with T cells.
  • T-cell proliferation, differentiation, and effector functions were assessed.
  • Inhibitors targeting indoleamine-2,3-dioxygenase, adenosine 2A Receptor, prostaglandin E2, and TGFβR were used.
  • A novel human tissue-based in situ assay was developed.

Main Results:

  • Human FRCs suppressed both naive and pre-activated T-cell proliferation and skewed differentiation.
  • FRCs employed four simultaneous mechanisms: IDO, A2AR, PGE2, and TGFβR.
  • A cocktail of inhibitors targeting these four pathways reversed FRC-mediated suppression.
  • Chimeric antigen receptor (CAR) T cells retained effector functions in the presence of FRCs.

Conclusions:

  • Human FRCs act as a regulatory checkpoint for T-cell activation through a four-part molecular mechanism.
  • Pharmacological targeting of FRCs offers potential strategies to enhance T-cell responses in infection and cancer.
  • The findings provide a basis for developing novel immunotherapies by modulating the FRC-T cell interaction.