Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment

Abstract

Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells. However, how persisting virus impacts various CD8 T-cell effector functions and influences other aspects of CD8 T-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. Using different strains of lymphocytic choriomeningitis virus (LCMV), we compared responses to the same CD8 T-cell epitopes during acute or chronic infection. Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues. Most importantly, CD8 T-cell functional impairment occurred in a hierarchical fashion in chronically infected mice. Production of interleukin 2 and the ability to lyse target cells in vitro were the first functions compromised, followed by the ability to make tumor necrosis factor alpha, while gamma interferon production was most resistant to functional exhaustion. Antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.Considerable evidence suggests that an effective CD8 T-cell response can control or eradicate viral infections. CD8 T cells appear to be particularly important in the immune response to chronic infections and in the long-term control of latent and reactivating viruses (2, 26). Indeed, potent human immunodeficiency virus (HIV)-specific CD8 T-cell responses correlate with acute viral control and long-term nonprogression (16,42,55,56,61,66). Further, rhesus macaques infected with simian immunodeficiency virus (SIV) show significantly higher viral loads if CD8 T cells are eliminated by antibody-mediated depletion (38). Evidence also suggests that CD8 T cells are important for the acute phase as well as long-term control of other persistent viruses, such as Epstein-Barr virus (EBV), cytomegalovirus, hepatitis B virus (HBV), and hepatitis C virus (HCV) (18,24,63,83). However, in many patients CD8 T cells fail to contain viral replication, particularly during HIV, HBV, and HCV infections. Recent studies suggest that functional impairment (exhaustion) and/or physical deletion of CD8 T cells can accompany ineffective viral control (44, 85). However, the impact of chronic viral infection on the induction and m...

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

“…et al [55] showed the presence of EBNA-specific CD62L 1 T cells in PB. By sorting EBV-specific T cells based on CCR7 expression we could confirm and extend previous studies [30,52,56] showing that the CCR7 1 central memory T cells serve as reservoir for EBV-specific effector T cells (Fig. 2D).…”

“…In line with our findings two previous studies could show that EBV-specific CCR7 1 CD4 1 and CD8 1 T cells are detectable in PB and predominately express IL-2 (Amyes et al [52] and Mallard et al [54]) and a study by Heller et al [55] showed the presence of EBNA-specific CD62L 1 T cells in PB. By sorting EBV-specific T cells based on CCR7 expression we could confirm and extend previous studies [30,52,56] showing that the CCR7 1 central memory T cells serve as reservoir for EBV-specific effector T cells (Fig. 2D).…”

Effector CD8 T cells dedifferentiate into long-lived memory cells

“…Effector and memory antigen-specific CD8 T cells were identified and purified by Fluorescence Activated Cell Sorting (FACS) using H-2D b tetramers bound to LCMV peptide GP33-41 conjugated to a fluorophore, along with CD8, CD44, CD127, Klrg1 and CD62L-fluorophore conjugated antibodies as previously described. 11,14,25,26 . To generate LCMV-specific CD8 T cell chimeras, transgenic P14 CD8 T cells with an engineered TCR that recognize the epitope GP33-41 of LCMV were harvested from naïve P14 TCR transgenic mice and adoptively transferred intravenously to C57BL/6 mice (cell# / mouse is specified in the figure legend) 11,27–29 .…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…A lack of methylation in the PD-1 promoter region has also been observed among antigen-specific CD8 T-cells from HIV patients which have been treated long-term (>2 years) with anti-retroviral therapy or in elite controllers 66 What remains unknown, however, is when T-cells undergo this differentiation. The incremental appearance of T-cells with an "exhausted" phenotype led to the conclusion that prolonged exposure to antigen and inflammation causes a progressively occurring acquisition of an exhausted phenotype 68 . Of note, this progression has only been described at the level of the entire population of antigen-specific T-cells but a direct demonstration that a T-cell, which at an early phase of a chronic infection displayed a normal phenotype, shows an exhausted phenotype at a later stage has not yet been performed.…”