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Acquired T cell dysfunction is a hallmark of chronic lymphocytic leukemia (CLL), and is linked to an increased risk of infections, but also reduced immune surveillance and disappointing responses to autologous T cell-based immunotherapy. The mechanisms of T cell dysfunction in CLL are not well understood. Studying immunity against chronic viruses allows for detailed analysis of the effect of CLL on T cells chronically exposed to a specific antigen. Cytomegalovirus (CMV) reactivations are rare in CLL, which corroborates with preserved CMV-specific T cell function. Epstein-Barr virus (EBV) is another herpesvirus that results in chronic infection, but unlike CMV, is characterized by subclinical reactivations in CLL patients. Since both herpesviruses induce strong CD8 + T cell responses, but have different clinical outcomes, studying these specific T cells may shed light on the mechanisms of CLL-induced T cell dysfunction. We first analyzed the phenotype of EBV-specific CD8 + T cells in CLL and healthy controls, and found that in CLL EBV-specific CD8 + T cells are in an advanced differentiation state with higher expression of inhibitory receptors. Secondly, CLL-derived EBV-specific CD8 + T cells show reduced cytotoxic potential, in contrast to CMV-specific T cells. Finally, we performed transcriptome analysis to visualize differential modulation by CLL of these T cell subsets. While T cell activation and differentiation genes are unaffected, in EBV-specific T cells expression of genes involved in synapse formation and T cell exhaustion is altered. Our findings on the heterogeneity of antigen specific T cell function in CLL aids in understanding immune-dysregulation in this disease., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)