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

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.

SUBMITTER: Hofland T

PROVIDER: S-EPMC7162091 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hepatitis C virus (HCV) readily sets up persistence in a large fraction of infected hosts. Mounting epidemiological and immunological evidence suggest that HCV's persistence could influence immune responses toward unrelated pathogens and vaccines. Nonetheless, the fundamental contribution of the inflammatory milieu during persistent HCV infection in impacting immune cells specific for common pathogens such as CMV and EBV has not been fully studied. As the co-regulatory receptors PD-1, Tim-3, and 2B4 have all been shown to be vital in regulating CD8(+) T cell function, we assessed their expression on CMV/EBV-specific CD8(+) T cells from patients with chronic hepatitis C (CHC) and healthy controls ex vivo and upon stimulation with virus-specific peptides in vitro. Total and CMV/EBV-specific CD8(+) T cells expressing PD-1, Tim-3, and 2B4 were highly enriched in patients with CHC compared to healthy individuals ex vivo. In vitro peptide stimulation further potentiated the differential co-regulatory receptor expression of PD-1, Tim-3, and 2B4, which then culminated in an enhanced functionality of CMV/EBV-specific CD8(+) T cells in CHC patients. Comprehensively analyzing plasma cytokines between the two cohorts, we observed that not only was IFN?-2a dominant among 21 other inflammatory mediators elevated in CHC patients but it also correlated with PD-1 and Tim-3 expressions ex vivo. Importantly, IFN?-2a further caused upregulation of these markers upon in vitro peptide stimulation. Finally, we could prospectively study patients receiving novel IFN-free antiviral therapy. Here, we observed that treatment-induced clearance of HCV resulted in a partial reversion of the phenotype of CMV/EBV-specific CD8(+) T cells in patients with CHC. These data reveal an alteration of the plasma concentrations of IFN?-2a together with other inflammatory mediators during CHC, which appeared to pervasively influence co-regulatory receptor expression on CMV/EBV-specific CD8(+) T cells.

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

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