Targeting Expanded Follicular Regulatory T Cells Is a New Approach to Combat Follicular Lymphoma

Follicular regulatory T cells (Tfr) are a potential target in treating follicular lymphoma (FL), the most common indolent B-cell lymphoma, according to study results published in Frontiers in Immunology.

FL is characterized by the uncontrolled proliferation of B cells within a specialized microenvironment resembling the germinal centers (GC) found in healthy lymph nodes. This microenvironment is crucial for the survival and expansion of malignant B cells, supported by complex interactions with various immune cells, including Tfr and follicular helper T cells (Tfh).

“Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the Tfr compartment, is still sparse,” explained Stephane Rodriguez, Unité Mixte de Recherche (UMR)1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer in Rennes, France, and coauthors.

The findings showed that Tfr cells are significantly expanded in FL compared with normal lymphoid tissues. In FL lymph nodes (LN), Tfr cells accounted for 13.7% ± 3.3% of CD4+ T cells, substantially increasing from the 4.3% ± 0.5% observed in non-malignant tonsils. This expansion was driven primarily by cells expressing the Tfr phenotype, characterized by Foxp3+CXCR5+ expression, which constituted 8.07% ± 8.06% of CD4+ T cells in FL LN, compared with 1.91% ± 0.21% in tonsils. These cells also exhibited a strong correlation between Foxp3 and CD25 expression, with the CD25+ subpopulation being the major contributor to Tfr expansion, representing 17.5% ± 10.7% of CD4+ T cells in FL LN.

Tfr cells in FL share a common progenitor with Tfh cells, as evidenced by overlapping T-cell receptor (TCR) repertoires. The overlap between FL-Tfh and FL-Tfr was 9% among the 1,000 most abundant TCR clones, indicating a clonally related origin. This shared origin suggests that Tfr cells may arise from similar developmental pathways as Tfh cells.

Functionally, Tfr cells efficiently inhibited CD8+ T cell proliferation and cytokine production. In vitro experiments showed that the addition of Tfr to FL CD8+ T cells reduced their proliferation index, resulting in significantly lower levels of IFN-γ (8.86 ± 6.87 pg/ml) and IL-2 (6.53 ± 2.80 pg/ml) compared with cultures without Tfr. However, Tfr had little impact on the support that Tfh cells provide to FL-B cells, which continued to proliferate despite Tfr presence.

“Altogether, these findings uncover the role of Tfr in the FL niche and may be useful to gain knowledge on lymphomagenesis and its therapeutic management,” concluded the study authors.

Reference
Rodriguez S, Alizadeh M, Lamaison C, et al. Follicular lymphoma regulatory T-cell origin and function. Front Immunol. 2024;15:1391404. doi:10.3389/fimmu.2024.1391404