Presence of Effector CD8+ T Cells in Hepatitis C Virus-Exposed Healthy Seronegative Donors

Abstract

CTL responses against multiple hepatitis C virus (HCV) epitopes were detected in 7 of 29 (24.1%) healthy family members (HFM) persistently exposed to chronically HCV-infected patients (HCV-HFM). These precursor CTL were at very low or undetectable frequencies, as determined by limiting dilution analysis. However, when HCV-specific effector CD8+ T cells, freshly isolated from PBMC of HCV-HFM, were assessed by a sensitive enzyme-linked immunospot assay, their frequencies were severalfold higher than those of precursor CTL. These results indicate that the two assays detect two functionally distinct T cell populations and that the effector cells are not assayed by the 51Cr-release assay. Furthermore, the combination of cell depletion and enzyme-linked immunospot analyses showed that the effector cells were confined into a CD8+ CD45RO+ CD28− population. The persistence of effector CD8+ T cells specific for both the structural and nonstructural viral proteins in uninfected HCV-HFM, suggest that: 1) an immunological memory is established upon a subclinical infection without any evidence of hepatitis, in a large cohort of HCV-exposed individuals; 2) because these cells required neither restimulation nor the addition of particular cytokines in vitro for differentiating in effectors, they should be capable of prompt HCV-specific effector function in vivo, possibly providing antiviral protection; and 3) the maintenance of effector T cell responses may be sustained by persisting low-level stimulation induced by inapparent infections.

Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments

“…Except for IFNγ, released cytokine levels in seronegative Group 2 individuals were indistinguishable from those in the control Group 1 ( Figure 1B ), and median IGRA responses in Group 2 were lower than in seropositive Group 3 and 5 individuals ( Table 1 ). These lower cellular responses in individuals that fail to show sero-conversion has previously already been described in a much larger cohort study in C. burnetii -exposed individuals ( 31 ) as well as in individuals exposed to HIV ( 35 – 37 ), HBV ( 38 ), HCV ( 39 ), HSV-2 ( 40 ) and SARS-CoV-2 ( 41 , 42 ).…”

Exposed seronegative: Cellular immune responses to SARS-CoV-2 in the absence of seroconversion

“…Canonically, adaptive immune responses appear one to two months after infection (27), and both CD4 + and CD8 + T-cells are associated with control (26). In individuals exposed to HCV via a family member, Scognamiglio et al (1999) identified CD8 + T-cells targeting both structural and non-structural proteins (NSPs) (16). There was no correlation between magnitude of response and mode of exposure, suggesting that similar cellular responses are generated following HCV exposure through different routes.…”

“…These patients, despite exposure to HIV and measurable cellular immunity, failed to develop an antibody response and were therefore classified as "exposed seronegative" (ESN). In the 30 years since initial reports in HIV, the phenomenon has been appreciated to occur following exposure to Hepatitis C virus (HCV), Hepatitis B virus (HBV), and Herpes Simplex virus 2 (HSV-2) (8,(15)(16)(17)(18), and recently Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), a pathogen to which most of the global population has been exposed (7,19,20). SARS-CoV-2, a member of the Coronaviridae family, is the causative agent of coronavirus disease 2019 .…”

Neonatal Exposure to Hepatitis C Virus Antigens in Uninfected Children Born to Infected Mothers

“…Consequently, the frequency of pre‐ and perinatal HCV exposure may be higher than previously reported. HCV‐specific CMI responses in seronegative and nonviremic individuals have been described in populations at risk for HCV exposure, such as healthy family members (19), siblings of infected children (20), spouses (21), health care workers (22), and people who inject drugs (23).…”