KLRG1 Impairs CD4+ T Cell Responses via p16ink4a and p27kip1 Pathways: Role in Hepatitis B Vaccine Failure in Individuals with Hepatitis C Virus Infection

Abstract

Co-infection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. HBV vaccine responses in HCV-infected individuals, however, are often blunted when compared to uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in regulation of CD4+ T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was over-expressed on CD4+ T cells from HCV-infected, HBV vaccine non-responders (HBV-NR) compared to those responders (HBV-R). The capacity of CD4+ T cell to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement of CD4+ T cell proliferation and IL-2 production in HCV-infected, HBV-NR in response to T cell receptor (TCR) stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser473) and decreased the expression of cell cycle inhibitors p16ink4a and p27kip1, which subsequently enhanced CDK 2 and cyclin E expressions. These results suggest that the KLRG1 pathway impairs CD4+ T cell responses to neo-antigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.

Forging a signature of in vivo senescence

“…But, are p16 INK4A -expressing lymphocytes senescent? There is considerable scepticism in the immunology community regarding whether these hyporeplicative lymphocytes are senescent, exhausted or otherwise dysfunctional 100,103,[109][110][111][112][113] , with some investigators claiming that such cells are capable of re-entering the cell cycle when isolated and appropriately stimulated in culture 110,111 . Importantly, hyporeplicative T cells that accumulate with age do not robustly express other markers of senescence, such as SASP or SAHFs, and their numbers are difficult to quantify, extending the uncertainty of how they should be classified.…”

T cell immunity and caregiving stress in young and older caregivers

“…Caregiving stress in these situations may prevent the immune system from mounting an adequate response. Thus, the higher percentage of KLRG1 -T cells in caregivers and controls presents a potential mechanism for the poorer vaccination responses previously reported in caregivers [43].…”

“…This higher percentage of functionally impaired T cells rich in inhibitory receptors such as KLRG-1 may explain the poorer vaccination response observed in caregivers [19,21,22]. It is known that KLRG-1 prevents the response of CD4 + T cells to novel antigens [43] necessary for achieving adequate immune protection following vaccination. Further, epigenetic studies lend support for this target-specific effect of caregiving stress on those T cells expressing this senescence marker in caregivers, regardless of their age.…”

Distinct CD55 Isoform Synthesis and Inhibition of Complement-Dependent Cytolysis by Hepatitis C Virus

“…An association with persistent infection, including cytomegalovirus, cryptococcus, and tuberculosis is more common in HCV-infected patients compared to non-HCV-infected controls (44). Further, HAV or HBV vaccination response is reduced in chronic HCV patients (45–49). These observations suggest that chronic HCV infection may generate an overall attenuation or suppression of immune responses.…”