Persistent hepatitis C virus (HCV) infection impairs HCV‐specific cytotoxic T cell reactivity through Mcl‐1/Bim imbalance due to CD127 down‐regulation

Abstract

In persistent hepatitis C virus (HCV) infection, HCV-specific cytotoxic T lymphocyte (CTL) reactivity is impaired and this affects HCV control. Interleukin-7 receptor (CD127) expression on these cells could regulate CTL reactivity through Mcl-1/Bim balance modulation. Bim is a pro-apoptotic molecule blocked by the action of Mcl-1. Mcl-1/Bim expression and T cell reactivity on HCV-specific CTLs were compared according to CD127 phenotype. Peripheral blood lymphocytes (PBL) from HLA-A2(+) HCV(+) patients were obtained. HCV-specific CTLs were visualized by staining PBL with anti-CD8 and HLA-A2/peptide pentameric complexes (pentamer). Mcl-1/Bim/CD127 phenotype of HCV-specific CTLs was tested by staining detectable CD8(+)/pentamer(+) cells with anti-Mcl-1/Bim/CD127 antibodies. HCV-specific CTL proliferation ability after specific in vitro challenge was tested in the presence and absence of pancaspase inhibitor z-VAD-fmk. All stained cells were analysed by flow cytometry. CD127(low)-expressing HCV-specific CTLs associated with high HCV viraemia, while CD127(high) correlated with undetectable viral loads (P < 0.001). Directly ex vivo, pentamer(+) cell frequency was similar according to CD127 expression level. Nevertheless, CD127(low) pentamer(+) cell proliferation after specific in vitro challenge was impaired (P < 0.05), although this was corrected by z-VAD-fmk treatment (P < 0.05). Mcl-1 expression was low directly ex vivo (P < 0.01), and Bim was up-regulated after antigen encounter (P < 0.05) of CD127(low) pentamer(+) cells. The ex vivo difference between Mcl-1 and Bim expression on pentamer(+) cells correlated positively with CD127 expression level (P < 0.001) and with pentamer(+) cell reactivity (P < 0.05). In summary, a low ex vivo Mcl-1 expression and Bim up-regulation after antigen encounter are involved in CD127(low) HCV-specific CTL hyporeactivity during chronic infection, but it can be overcome by apoptosis blockade.

Dying to protect: cell death and the control of T‐cell homeostasis

“…In chronic infection, Mcl-1 is downregulated in CD127 low antigen specific CTLs along with up-regulation of Bim and this causes apoptosis of CD8 + T cells (272) or hyporeactivity of CTLs, which could possibly be treated by apoptosis inhibition or IL-7 treatment (273). Conversely, Mcl-1 enhances survival in a variety of cancers including T cell lymphomas and various Mcl-1 inhibitors are being explored (274).…”

Hepatitis C virus infection in children and adolescents

“…Major obstacles to HCV vaccine development are the diversity of the virus, the ability of the virus to evade the immune response in infected individuals with high rates of mutation, and development of “quasispecies,” which are distinct but closely related HCV variants that can be present in a single individual 5, 137, 142. Additional immune‐evading strategies that have been identified include antibody avoidance, cytotoxic T lymphocyte escape, and a failure to initiate an appropriate T cell response during the beginning of infection, among others 143, 144, 145, 146, 147, 148. Despite these challenges, several investigations have demonstrated success in preclinical animal studies showing induction of both humoral and cellular immunity against HCV 149, 150.…”

Adaptive T-Cell Response in Pathogenesis of Hepatitis C Infection

“…Исследования последних лет показали, что Т-клетки пациентов с ХГС характеризуются по-вышенной экспрессией ингибиторных молекул Bim [31] -3 и PD-1 [18]. Вы-явление молекулярных мишеней, опосредующих выключение функций ЦТЛ, представляет боль-шой интерес в плане разработки новых страте-гий восстановления иммунного ответа при ХГС, основанных на блокировании коингибиторных молекул.…”