TY - JOUR
T1 - EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4 + T cells in chronic lymphocytic leukemia
AU - Roessner, Philipp M
AU - Llaó Cid, Laura
AU - Lupar, Ekaterina
AU - Roider, Tobias
AU - Bordas, Marie
AU - SCHIFFLERS, Christoph
AU - Arseni, Lavinia
AU - Gaupel, Ann-Christin
AU - Kilpert, Fabian
AU - Krötschel, Marit
AU - Arnold, Sebastian J.
AU - Sellner, Leopold
AU - Colomer, Dolors
AU - Stilgenbauer, Stephan
AU - Dietrich, Sascha
AU - Lichter, Peter
AU - Izcue, Ana
AU - Seiffert, Martina
N1 - Funding Information:
Acknowledgements This study was supported by the German Research Foundation (DFG) project EV-RNA (SE 2331/2-1), the Eurostars project E!10865—LeukeMab (01QE1716) as part of the Horizon 2020 EU funding framework, and by the German José Car-reras Foundation (grant 13R/2018) to MS. PMR was supported by the German Cancer Aid grant number 112069 and has been funded by a fellowship of the DKFZ Clinician Scientist Program, supported by the Dieter Morszeck Foundation. EL and AI were supported by Bundes-ministerium für Bildung und Forschung (grant BMBF 01 EO 1303), and EL, FK, MK, and AI were supported by the Max Planck Society. SJA was supported by the German Research Foundation (AR 732/2-1, AR 732/3-1), project A03 of SFB 850 (project ID 89986987), and Germany’s Excellence Strategy (CIBSS—EXC-2189—Project ID 390939984). DC was supported by the Spanish Ministry of Economy and Competitiveness (SAF 15/31242R) and the Generalitat de Cata-lunya (2017 SGR 1009). SS was supported by DFG SFB1074 subproject B1. SD was supported by a grant of the Hairy Cell Leukemia Foundation, the Heidelberg Research Centre for Molecular Medicine (HRCMM), and an e:med BMBF junior group grant.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/2/1
Y1 - 2021/2/1
N2 - The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2-/- mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.
AB - The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2-/- mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.
UR - https://www.scopus.com/pages/publications/85100100502
U2 - 10.1038/s41375-021-01136-1
DO - 10.1038/s41375-021-01136-1
M3 - Article
SN - 0887-6924
VL - 35
SP - 2311
EP - 2324
JO - Leukemia
JF - Leukemia
IS - 8
ER -
