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Activation and expansion of T-follicular helper cells in chronic lymphocytic leukemia nurselike cell co-cultures

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Alicia M. Vaca, Nikolaos Ioannou, Mariela Sivina, Elisavet Vlachonikola, Karen Clise-Dwyer, Ekaterina Kim, Dan Li, Qing Ma, Alessandra Ferrajoli, Zeev Estrov, William G. Wierda, Piers E.M. Patten, Alan G. Ramsay, Jan A. Burger

Original languageEnglish
Pages (from-to)1324-1335
Number of pages12
JournalLeukemia
Volume36
Issue number5
Early online date11 Feb 2022
DOIs
Accepted/In press31 Jan 2022
E-pub ahead of print11 Feb 2022
PublishedMay 2022

Bibliographical note

Funding Information: The authors are grateful to all the patients who provided samples for this study. They also thank Kostas Stamatopoulos for contributing data from the TR clonotype database held at the Institute of Applied Biosciences at CERTH and for critical reading the paper. The authors thank the Nikon Imaging Facility at King ’ s College London. The Advanced Cytometry & Sorting Core Facility at MD Anderson is supported by NCI P30CA016672. PEMP is supported by MRC Grant MR/T005106/1. This work was supported by the ERA-NET on Translational Cancer Research (TRANSCAN-2) project code 5041673 (EV) and the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program (JAB), and in part by CLL Global Research Foundation grants (JAB). TM Funding Information: The authors are grateful to all the patients who provided samples for this study. They also thank Kostas Stamatopoulos for contributing data from the TR clonotype database held at the Institute of Applied Biosciences at CERTH and for critical reading the paper. The authors thank the Nikon Imaging Facility at King? s College London. The Advanced Cytometry & Sorting Core Facility at MD Anderson?is supported by NCI P30CA016672. PEMP is supported by MRC Grant MR/T005106/1. This work was supported by?the ERA-NET on Translational Cancer Research (TRANSCAN-2)?project code?5041673 (EV) and?the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots ProgramTM(JAB), and in part by CLL Global Research Foundation grants (JAB). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

King's Authors

Abstract

Interactions between chronic lymphocytic leukemia (CLL) cells and T-cell subsets in the lymph node microenvironment are thought to play a central role in disease biology. To study these interactions in a model of the CLL lymph node microenvironment, we characterized T-cell subsets in CLL nurselike cell (NLC) co-cultures. We focused on T-follicular helper (Tfh) cells, which are characterized by CXCR5 expression and localization to B-cell follicles. In co-cultures from 28 different CLL patients, we detected an expansion of Tfh cells based on PD-1, BCL6, and ICOS expression, with increased IL-21 and downmodulated CD40L surface expression. Regulatory T cells (Treg), which promote immune tolerance, also expanded in NLC co-cultures. T-cell receptor (TR) gene repertoire analyses confirmed the clonal expansion of CD4+ T cells, with an enrichment of TR clonotypes commonly expanded also in primary CLL samples. Multicolor confocal microscopy revealed that Tfh, but not Treg co-localize with proliferating CLL cells in CLL lymph node sections. Collectively, these data provide new insight into the cellular and molecular cross-talk between CLL and T-cell subsets, resulting in clonal expansion of T-helper cells and interaction of Tfh cells with proliferating CLL cells which may open new avenues for therapeutic targeting.

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