Abstract
IntroductionEpidemiological data suggest that persistent viral infections impair immune homeostasis and immune responsiveness. Previous studies showed that chronic virus infections negatively impact bystander T‐cell differentiation and memory formation but there is limited knowledge of how chronic virus infections impinge on heterologous naive T‐cell populations.MethodsWe used adoptive transfer of naive CD8 T cells with defined nonviral specificity into hosts, which were subsequently chronically infected with lymphocytic choriomeningitis virus, followed by analyses of numeric, phenotypic, and functional changes provoked in the chronically infected host.ResultsWe demonstrate that chronic virus infections have a profound effect on the number and phenotype of naive bystander CD8 T cells. Moreover, primary expansion upon antigen encounter was severely compromised in chronically infected hosts. However, when naive bystander CD8 T cells were transferred from the chronically infected mice into naive hosts, they regained their expansion potential. Conversely, when chronically infected hosts were supplied with additional antigen‐presenting cells (APCs), primary expansion of the naive CD8 T cells was restored to levels of the uninfected hosts.ConclusionsOur results document numeric, phenotypic, and functional adaptation of bystander naive CD8 T cells during nonrelated chronic viral infection. Their functional impairment was only evident in the chronically infected host, indicating that T‐cell extrinsic factors, in particular the quality of priming APCs, are responsible for the impaired function of naive bystander T cells in the chronically infected hosts.
Highlights
Epidemiological data suggest that persistent viral infections impair immune homeostasis and immune responsiveness
We performed similar experiments where mice were infected with murine cytomegalovirus (MCMV), which causes a latent infection with sporadic stages of reactivation (Figure S1A)
In lymphocytic choriomeningitis virus (LCMV) infection, infected fibroblastic reticular cells are killed by CD8 T cells,[17] which could potentially compromise survival niches for naive CD8 T cells leading to their numerical reduction
Summary
During primary T‐cell responses, activated T cells clonally expand and form an effector pool as well as a long‐lived memory population.[1,2] There is epidemiological evidence that persistent viral infections like hepatitis C virus (HCV), human immunodeficiency virus (HIV), and lymphocytic choriomeningitis virus (LCMV) infection in mice functionally impair CD8 T cells in their immune responsiveness.[3]. In patients with chronic HCV infection, naive T cells express phenotypical markers that are associated with memory and diminished levels of CD5,9 which correlates with a lower threshold for T‐cell receptor (TCR) signaling. This effect was reported to be transient, since these alterations could be reversed within 2 years following successful therapy.[9] Chronic virus infections impair T‐cell differentiation of tumor‐specific CD8 T cells, leading to a diminished tumor control.[10]. These impairments can be reversed when bystander cells are transferred into uninfected hosts, indicating that T‐cell extrinsic cues caused by the chronic virus restrict their functional potential
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