AbstractGenome-wide association studies identified a single-nucleotide polymorphism (SNP) affecting the transcription factor Eomesodermin (EOMES) associated with a significantly increased risk to develop chronic lymphocytic leukemia (CLL). Epigenetic analyses, RNA sequencing, and flow cytometry revealed that EOMES is not expressed in CLL cells, but in CD8⁺ T cells for which EOMES is a known master regulator. We thus hypothesized that the increased CLL risk associated with the EOMES SNP might be explained by its negative impact on CD8⁺ T-cell-mediated immune control of CLL. Flow cytometry analyses revealed a higher EOMES expression in CD8⁺ T cells of CLL patients compared to healthy individuals, and an accumulation of PD-1⁺ EOMES⁺ CD8⁺ T cells in lymph nodes rather than blood or bone marrow in CLL. This was in line with an observed expansion of EOMES⁺ CD8⁺ T cells in the spleen of leukemic Eµ-TCL1 mice. As EOMES expression was highest in CD8⁺ T cells that express inhibitory receptors, an involvement of EOMES in T-cell exhaustion and dysfunction seems likely. Interestingly, Eomes-deficiency in CD8⁺ T cells resulted in their impaired expansion associated with decreased CLL control in mice. Overall, these observations suggest that EOMES is essential for CD8⁺ T-cell expansion and/or maintenance, and therefore involved in adaptive immune control of CLL.