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 (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.
Highlights
Despite abundant phenotypical data characterizing CD4+ T cells in chronic lymphocytic leukemia (CLL), their role in disease development and progression is controversial and poorly understood [1]
Cytotoxic EOMES+ PD-1+ TR1-like CD4+ T cells accumulate in lymph nodes (LNs) of CLL patients
According to published data [1, 6, 8,9,10, 33,34,35], we observed an accumulation of PD-1-expressing CD4+ T cells in blood samples of patients with CLL or DLBCL in comparison to healthy controls (HC) (Supplementary Fig. 1A–E), and subsequently aimed to characterize these cells
Summary
Despite abundant phenotypical data characterizing CD4+ T cells in chronic lymphocytic leukemia (CLL), their role in disease development and progression is controversial and poorly understood [1]. Besides the well-known T helper (Th) cell subsets [1], interleukin (IL-)10-producing, FOXP3− CD4+. TR1 cells are described as IL-10-induced cells that produce IL-10 and harbor cytotoxic activity, and express several co-inhibitory receptors such as programmed cell death protein-1 (PD-1) [5].
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