Abstract
The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells.
Highlights
The CD8 T cell immune response is an important component of the adaptive immunesystem
To analyze the kinetics of the expression of T cell factor 1 (TCF1) in CD8 T cells and its correlation with CD8 T cell functions during lymphocytic choriomeningitis virus (LCMV) chronic infection, P14 cells (CD45.1) expressing a GP33-specific transgenic T cell receptor were adoptively transferred into CD45.2 congenic wild-type (WT) C57BL/6J mice, recipients were infected with LCMV clone 13 strain (Cl13) at 1 day after transfer
The results showed a sustained increase in the proportion of the TCF1high population of P14 cells over time during chronic infection, and the percentage of TCF1high P14 cells reached approximately 20% at the advanced stage (D30) of LCMV chronic infection (Figure 1A)
Summary
The CD8 T cell immune response is an important component of the adaptive immunesystem. TCF1 Regulates Exhausted CTL Function acute viral infection, the majority of effector CD8 T cells die by means of apoptosis after antigen clearance; only ∼5–10% of the cells survive and differentiate into memory CD8 T cells to establish long-term immune protection [2]. Viruses, such as HIV (human immunodeficiency virus), HBV (Hepatitis B virus), and HCV (Hepatitis C virus), evolved multiple strategies to escape from the surveillance of the immune system [3]. As a result, those pathogens cannot be cleared effectively and achieve a high viral load in the host, placing CD8 T cells under sustained antigen exposure, and eventually leading to CD8 T cell exhaustion
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