Persistent gamma delta T‐cell dysfunction in chronic HCV infection despite direct‐acting antiviral therapy induced cure

Abstract

Immune dysfunction is a hallmark of chronic HCV infection and viral clearance with direct antivirals recover some of these immune defects. TCRVγ9Vδ2 T‐cell dysfunction in treated HCV patients however is not well studied and was the subject of this investigation. Peripheral blood cells from patients who had achieved sustained virologic response (SVR) or those who had relapsed after interferon‐free therapy were phenotyped using flow cytometry. Functional potential of Vγ9Vδ2 T cells was tested by measuring proliferation in response to aminobisphosphonate zoledronic acid, and cytotoxicity against HepG2 hepatoma cell line. TCR sequencing was performed to analyse impact of HCV infection on Vδ2 T‐cell repertoire. Vγ9Vδ2 cells from patients were activated and therapy resulted in reduction of CD38 expression on these cells in SVR group. Relapsed patients had Vδ2 cells with persistently activated and terminally differentiated cytotoxic phenotype (CD38+CD45RA+CD27−CD107a+). Irrespective of outcome with therapy, majority of patients had persistently poor Vδ2 T‐cell proliferative response to zoledronate along with lower expression of CD56, which identifies anti‐tumour cytotoxic subset, relative to healthy controls. There was no association between the number of antigen reactive Vγ2‐Jγ1.2 TCR rearrangements at baseline and levels of proliferation indicating nonresponse to zoledronate is not due to depletion of phosphoantigen responding chains. Thus, HCV infection results in circulating Vγ9Vδ2 T cells with a phenotype equipped for immediate effector function but poor cytokine response and expansion in response to antigen, a functional defect that may have implications for susceptibility for carcinogenesis despite HCV cure.

Reversal of Immunity After Clearance of Chronic HCV Infection—All Reset?

“…Compared to conventional CD4 or CD8 T cells, unconventional T cells, such as γδ T cells and MAIT cells are typically rapid effector cells that respond within hours towards foreign antigens and/or other innate signals exhibiting important functions during viral infection ( 6 , 64 , 65 ). In chronic hepatitis C, γδ T cells are less efficient in producing cytokines and exhibit an activated phenotype ( 41 , 66 ). Whereas the activated phenotype vanished upon DAA-mediated HCV clearance, the dysfunction remained ( 41 ).…”

“…In chronic hepatitis C, γδ T cells are less efficient in producing cytokines and exhibit an activated phenotype ( 41 , 66 ). Whereas the activated phenotype vanished upon DAA-mediated HCV clearance, the dysfunction remained ( 41 ). This dysfunction was not due to a skewing in the T cell receptor repertoire as it was shown to be unaltered in patients with chronic hepatitis C and further remained stable after elimination of HCV ( 40 ).…”

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

“…361 One recent study showed that gamma delta T cell dysfunction in chronic HCV infection is not reversed after HCV cure by DAAs, indicating this functional defect may have implications for susceptibility to HCC. 362 Burchill et al showed that DAAs therapy results in (i) the reconstitution of lymphocyte populations in the peripheral blood; (ii) re-differentiation of memory T cells towards an effector phenotype; (iii) a reduction in the expression of some, but not all inhibitory molecules on bulk and viral-specific CD8 T cell populations; and (iv) a reduction in the activation status of circulating NK cells. B cells are the source of humoral anti-HCV antibodies that are important in resolving HCV infection.…”

Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

“…We showed that the circulating Vδ2 T cells in patients who were cured of HCV with DAA remain dysfunctional. Patient Vδ2 T cells were activated and had poor proliferative response to phosphoantigens [ 12 ] and these defects did not normalize with virus clearance. Another study reported a similar fate of these cells in HIV/HCV co-infected patients [ 44 ].…”

“…This is also an excellent model system to study basic immunology questions such as plasticity of the immune system and epigenetic regulation of immune responses in chronic infections and their reversibility. Our group has conducted pioneer clinical trials of DAA for HCV cure [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ] and we investigate immune dysfunction in chronic HCV (CHC) and its recovery in cured individuals [ 9 , 10 , 11 , 12 , 13 , 14 ]. This focused review provides current understanding of innate and adaptive lymphocytes perturbations in CHC patients, the status of these immune cells after viral clearance with DAA, and implications thereof (summarized in Table 1 and in Figure 1 ).…”