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

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(R)1) cells. The T(R)1 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(R)1 cells with cytotoxic capacity accumulate also in E mu-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(R)1 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(R)1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.