EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4⁺ T cells in chronic lymphocytic leukemia.

ABSTRACT: 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 (T_R1) cells. The T_R1 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. T_R1 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 T_R1 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 T_R1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.

SUBMITTER: Roessner PM 

PROVIDER: S-EPMC8324479 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature