Functional Differences Between EBV- and CMV-Specific CD8+ T cells Demonstrate Heterogeneity of T cell Dysfunction in CLL

• Main Authors: Tom Hofland, Iris de Weerdt, Sanne Endstra, Aldo Jongejan, Laura Platenkamp, Ester B.M. Remmerswaal, Perry D. Moerland, Ineke J.M. ten Berge, Mark-David Levin, Arnon P. Kater, Sanne H. Tonino
• Format: Article
• Language: English
• Published: Wolters Kluwer 2020-04-01
• Series: HemaSphere
• Online Access: http://journals.lww.com/10.1097/HS9.0000000000000337

Abstract. 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.