T follicular helper cell-mediated IL-21 production suppresses FOXP3 expression of T follicular regulatory-like cells in diffuse large B cell lymphoma patients.

Based on CD25 expression, T follicular helper cells (Tfh) could be divided into T follicular regulatory (Tfr)-like subset (CD25 ⁺ CD4 ⁺ CXCR5 ⁺ ) and CD25 ^- Tfh subset (CD25 ^- CD4 ⁺ CXCR5 ⁺ ). Patients with diffuse large B cell lymphoma (DLBCL) display high level of Tfr-like cells in blood and tumor. This Tfr-like subset could suppress CD8 T cell response while promote tumor cell proliferation. In this study, we investigated the transcription factors and regulatory elements associated with Tfr-like cells in DLBCL patients. Both circulating and tumor-infiltrating Tfr-like cells presented slightly higher Blimp-1 expression and significantly higher Foxp3 expression than the CD25 ^- Tfh subset. As the IL-2 receptor, CD25 could be moderately upregulated in stimulated CD25 ^- Tfh cells. However, stimulated CD25 ^- Tfh cells could not upregulate Foxp3, indicating that the distinction between Foxp3-low CD25 ^- CXCR5 ⁺ CD4 ⁺ T cells and Foxp3-high CD25 ⁺ CXCR5 ⁺ CD4 ⁺ T cells was not due to differences in stimulation status. Regarding cytokine production, while both Tfr-like and CD25 ^- Tfh cells upregulated IL-21 and IL-10 during stimulation, the CD25 ^- Tfh cells presented significantly higher IL-21 and lower IL-10 expression than the Tfr-like cells, and the TGF-β expression was only increased in Tfr-like cells. Interestingly, IL-21 secreted from CD25 ^- Tfh cells negatively regulated the expression of Foxp3 and IL-10 of autologous Tfr-like cells. Together, these results demonstrated that the Tfr-like and CD25 ^- Tfh subsets of circulating Tfh cells presented different functions and should be investigated separately.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)