Sustained Vd1 and Vd2 T-cell profiles in chronic viral hepatitis

Gamma delta (γ/δ) T cells represent a small population of innate-like lymphocytes that harbour adaptive and innate immune features. Subsets of γ/δ T cells are defined by their usage of different T-cell receptor γ and/or δ chains and exhibit characteristic tissue distributions. In peripheral blood, for example, the majority of human γ/δ T cells express the Vδ2 chain. In contrast, in tissues like the liver, human γ/δ T cells mainly carry the Vδ1 chain. γ/δ T cells sense early danger signals and can rapidly respond to several bacterial, viral and parasitic infections. Yet, only very little is known about the role, function and phenotype of the different γ/δ T cell subsets in the context of chronic viral hepatitis. It was therefore the goal of our study to generate γ/δ T-cell profiles with regard to their functionality in chronic Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection.

For this, we performed comprehensive flow cytometric analyses of peripheral blood γ/δ T cells obtained from individuals chronically infected with HBV (n = 19) or HCV (n = 20) compared to 20 healthy donors. The analyses covered activation state, functionality and differentiation including transcription factor profiles of circulating Vδ1 and Vδ2 expressing γ/δ T cells.

Vδ1 and Vδ2 T-cell subsets expressed high levels of the transcription factors Tbet and Eomes that are both essential for T-cell effector functions and differentiation. However, our results also revealed striking differences between these two γ/δ T-cell subsets. In particular, almost all Vδ1 T cells but only a minor fraction of Vδ2 T cells expressed Helios. It has been shown that the transcription factor Helios is up-regulated upon conventional T-cell activation and thus possibly reflects a higher activation status of Vδ1 compared to Vδ2 T cells. In line with this, a higher frequency of Vδ1 T cells expressed activation markers such as CD69 and CD38.

Interestingly, only Vδ2 T cells expressed the transcription factor PLZF in high frequencies, that is associated with an innate-like effector differentiation. This PLZF expression was accompanied by expression of CD161 and IL18Rα. In addition, Vδ2 T cells exhibited robust IFNγ and TNF production upon stimulation with IL-12, IL-15 and IL-18. Of note, this combination of phenotypic and functional features is characteristic for Mucosal-associated invariant T (MAIT) cells that also belong to innate-like lymphocytes. This similarity between Vδ2 T cells and MAIT cells may represent a safeguard mechanism of immediate immune responses by functional redundancy.

Importantly, the aforementioned phenotypic and functional profiles of Vδ1 and Vδ2 T-cell subsets remained stable despite chronic infections with HBV or HCV indicating intrinsic subset-defining programmes with limited plasticity.