Abstract
CXCR5 mediates homing of both B and follicular helper T (TFH) cells into follicles of secondary lymphoid organs. We found that CXCR5+CD8+ T cells are present in human tonsils and follicular lymphoma, inhibit TFH-mediated B cell differentiation, and exhibit strong cytotoxic activity. Consistent with these findings, adoptive transfer of CXCR5+CD8+ T cells into an animal model of lymphoma resulted in significantly greater antitumor activity than CXCR5−CD8+ T cells. Furthermore, RNA-Seq-based transcriptional profiling revealed 77 differentially expressed genes unique to CXCR5+CD8+ T cells. Among these, a signature comprised of 33 upregulated genes correlated with improved survival in follicular lymphoma patients. We also showed that CXCR5+CD8+ T cells could be induced and expanded ex vivo using IL-23 plus TGF-β, suggesting a possible strategy to generate these cells for clinical application. In summary, our study identified CXCR5+CD8+ T cells as a distinct T cell subset with ability to suppress TFH-mediated B cell differentiation, exert strong antitumor activity, and confer favorable prognosis in follicular lymphoma patients.
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Acknowledgments
We thank Dr. Stephen E Ullrich (University of Texas MD Anderson Cancer Center) for technical advice. This work is supported by grants from the Leukemia and Lymphoma Society Quest for Cure Grant (P-QFC-3068-14 to SSN), NIH National Institute of Allergy and Infectious Diseases (RO1AI109294 to SSW), Oversea Development Program (SWH2016HWHZ-01 to XL), and generous philanthropic contributions to the University of Texas MD Anderson Moon Shots Program. The South Campus Flow Cytometry and Cell Sorting Core Facility is supported by The University of Texas MD Anderson Cancer Center Support Grant from National Institutes of Health (P30 CA016672) and the Advanced Microscopy Core Facility is supported by National Institutes of Health grant 1S10 RR029552.
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FC and HL designed, conducted the experiments, analyzed the results, and wrote the manuscript; XL contributed to experimental design; JC, YM, JW, XC, ZW, and JW performed experiments; ZYJ and AL provided vital experimental materials. KB assisted in manuscript writing. WM, ZZ, JW, and RED assisted with RNA-Seq and data analysis; RED, WP, CY, CD, and SSW provided expertize. SSN supervised the project design and experimental interpretation, and is principal investigator of the laboratory in which this work was conducted. All authors were involved in manuscript preparation and approved the final version of the manuscript.
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SSN has received research support from Kite/Gilead, Celgene, Cellectis, Poseida, Merck, Acerta, Karus, and BMS; served as consultant and advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, and Merck. The remaining authors declare that they have no conflict of interest.
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Chu, F., Li, H.S., Liu, X. et al. CXCR5+CD8+ T cells are a distinct functional subset with an antitumor activity. Leukemia 33, 2640–2653 (2019). https://doi.org/10.1038/s41375-019-0464-2
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DOI: https://doi.org/10.1038/s41375-019-0464-2
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