Follicular lymphoma triggers phenotypic and functional remodeling of the human lymphoid stromal cell landscape

Highlights

• Phenotypic, transcriptomic, and functional characterization of human native LSC subsets

• CD49a highlights human LSC perivascular precursors and immunologically competent FRCs

• FL LSCs exhibit a pro-tumoral profile deregulating lymphoid chemokine expression

• FL B cells contribute to FL LSC polarization through TNF- and TGF-β-dependent pathways

Summary

Lymphoid stromal cells (LSCs) are essential organizers of immune responses. We analyzed tonsillar tissue by combining flow cytometry, in situ imaging, RNA sequencing, and functional assays, defining three distinct human LSC subsets. The integrin CD49a designated perivascular stromal cells exhibiting features of local committed LSC precursors and segregated cytokine and chemokine-producing fibroblastic reticular cells (FRCs) supporting B and T cell survival. The follicular dendritic cell transcriptional profile reflected active responses to B cell and non-B cell stimuli. We therefore examined the effect of B cell stimuli on LSCs in follicular lymphoma (FL). FL B cells interacted primarily with CD49a⁺ FRCs. Transcriptional analyses revealed LSC reprogramming in situ downstream of the cytokines tumor necrosis factor (TNF) and transforming growth factor β (TGF-β), including increased expression of the chemokines CCL19 and CCL21. Our findings define human LSC populations in healthy tissue and reveal bidirectional crosstalk between LSCs and malignant B cells that may present a targetable axis in lymphoma.