CD94/NKG2A Expression Is Associated with Proliferative Potential of CD8 T Cells during Persistent Polyoma Virus Infection

Abstract

Memory CD8 T cells comprise a critical component of durable immunity because of their capacity to rapidly proliferate and exert effector activity upon Ag rechallenge. During persistent viral infection, memory CD8 T cells repetitively encounter viral Ag and must maintain a delicate balance between limiting viral replication and minimizing immunopathology. In mice infected by polyoma virus, a natural mouse pathogen that establishes long-term persistent infection, the majority of persistence-phase antiviral CD8 T cells express the inhibitory NK cell receptor CD94/NKG2A. In this study, we asked whether CD94/NKG2A expression is associated with Ag-specific recall of polyoma virus-specific CD8 T cells. During the persistent phase of infection, polyoma virus-specific CD8 T cells that express CD94/NKG2A were found to preferentially proliferate; this proliferation was dependent on cognate Ag both in vitro and in vivo. In addition, CD94/NKG2A+ polyoma-specific CD8 T cells have a markedly enhanced capacity to produce IL-2 upon ex vivo Ag stimulation compared with CD94/NKG2A− polyoma-specific CD8 T cells. Importantly, CD94/NKG2A+ anti-polyoma virus CD8 T cells appear to be essential for Ag-specific recall responses in mice persistently infected by polyoma virus. Because of its higher proliferative potential and capacity to produce IL-2, we propose that the CD94/NKG2A+ subpopulation represents a less differentiated state than the CD94/NKG2A− subpopulation. Identification of proliferation-competent subpopulations of memory CD8 T cells should prove valuable in designing therapeutic vaccination strategies for persistent viral infections.

Cutting Edge: Engagement of NKG2A on CD8+ Effector T Cells Limits Immunopathology in Influenza Pneumonia

“…As previously noted, the impact of NKG2A ligation on CD8 ϩ T cell activity varies depending upon the experimental system but may also vary with the specific effector function examined. In polyoma infection, for example, engagement of CD8 ϩ T cell NKG2A/CD94 by Qa-1b on APC appeared to reduce cytotoxicity, whereas it enhanced the proliferative capacity and production of IL-2 by CD8 ϩ effector/memory cells (19). The hypothesis that NKG2A transduces an inhibitory signal, raising the threshold for T cell activation, would not account for these effects.…”

“…Although the mAb used to detect NKG2A (clone 20d5) also recognizes the NKG2 isoforms NKG2C and NKG2E, nearly all 20d5 mAbsorted, Ag-specific CD8 T cells predominantly express NKG2A transcripts (14,19,20). Furthermore, NKG2A and NKG2C expression appears to be mutually exclusive and clone specific (21,22), and CD94/NKG2C has not been shown to mediate activation of murine NK or CD8 T cells (18).…”

The Antiviral CD8+ T Cell Response Is Differentially Dependent on CD4+ T Cell Help Over the Course of Persistent Infection

“…ϩ T cells lose expression of CD94/NKG2A after Agdriven proliferation to alleviate the block to killing infected cells (65,66). It is interesting to speculate that PD-1 may play a counterbalancing effect to CD94/NKG2A by controlling secondary T cell effector differentiation.…”

Phenotypic and Functional Changes of Cytotoxic CD56posNatural T Cells Determine Outcome of Acute Hepatitis C Virus Infection

“…Chronic viral infections including HCV can modulate the expression of inhibitory and activating NKRs that fine-tune the activity of CD56 ϩ lymphocytes (6,10,11,15,17,28,29). However, little is known of these receptors in the acute HCV setting; we therefore examined the phenotype of NT cells in our patient cohort to determine whether altered NKR expression was associated with the outcome of acute HCV infection.…”