Distinct follicular T cell subsets regulate lymphoma progression and outcomes.

Follicular lymphoma (FL) is characterized by the expansion of neoplastic follicle structures and is suggested to have a distinctive form of T cell immunity. However, the heterogeneity and role of follicular T cells beyond T follicular helper (TFH) cells remain largely unexplored in FL. Here, we performed multi-omics analyses of follicular T cells in FL leveraging pan-cancer single-cell mapping, spatially resolved single-cell transcriptomics and multiplex protein profiling, and functional characterization. We identified transcriptionally and spatially distinct non-TFH follicular T cell subsets that expand in FL. These subsets exhibit enhanced anti-tumorigenic properties and form unique spatial niches. Their phenotypes were replicated under interleukin-21-predominant conditions, revealing discrete self-regulatory cellular ecosystems that generate these subsets and may underlie FL clinical behaviors. Furthermore, these subsets robustly stratify FL prognoses, independently of existing prognostic markers. Our findings highlight previously unrecognized immunity that could advance our understanding of lymphoma and improve patient management.