Upregulation of Interleukin 7 Receptor Alpha and Programmed Death 1 Marks an Epitope-Specific CD8+ T-Cell Response That Disappears following Primary Epstein-Barr Virus Infection

In immunocompetent individuals, the stability of the herpesvirus-host balance limits opportunities to study the disappearance of a virus-specific CD8⁺ T-cell response. However, we noticed that in HLA-A*0201-positive infectious mononucleosis (IM) patients undergoing primary Epstein-Barr virus (EBV) infection, the initial CD8 response targets three EBV lytic antigen-derived epitopes, YVLDHLIVV (YVL), GLCTLVAML (GLC), and TLDYKPLSV (TLD), but only the YVL and GLC reactivities persist long-term; the TLD response disappears within 10 to 27 months. While present, TLD-specific cells remained largely indistinguishable from YVL and GLC reactivities in many phenotypic and functional respects but showed unique temporal changes in two markers of T-cell fate, interleukin 7 receptor alpha (IL-7Rα; CD127) and programmed death 1 (PD-1). Thus, following the antigen-driven downregulation of IL-7Rα seen on all populations in acute IM, in every case, the TLD-specific population recovered expression unusually quickly post-IM. As well, in four of six patients studied, TLD-specific cells showed very strong PD-1 upregulation in the last blood sample obtained before the cells’ disappearance. Our data suggest that the disappearance of this individual epitope reactivity from an otherwise stable EBV-specific response (i) reflects a selective loss of cognate antigen restimulation (rather than of IL-7-dependent signals) and (ii) is immediately preceded, and perhaps mediated, by PD-1 upregulation to unprecedented levels.Virus-specific CD8⁺ T cells play a major role in controlling primary virus infections, but what determines the long-term fate of these cells is poorly understood (23, 31, 42). Studies of lymphocytic choriomeningitis virus (LCMV) infection in mice show that, where the virus is completely cleared in vivo, entry into and maintenance within the CD8 memory pool depends upon the homeostatic cytokine interleukin 7 (IL-7) and is restricted to LCMV-specific T cells that reacquire the high-affinity IL-7 receptor alpha (IL-7Rα; CD127) (22). However, in situations in which LCMV is not cleared, the virus-specific-T-cell pool never becomes fully IL-7Rα positive, and its maintenance depends upon chronic antigen stimulation rather than IL-7 (24, 36, 43). Furthermore, with ongoing virus replication, the LCMV-specific CD8⁺ T cells remain detectable but become functionally exhausted, responding poorly to antigen in ex vivo assays (16, 42, 44, 47). This is marked by the cells’ upregulation of programmed death 1 (PD-1), one member of the CD28 family of proteins that modulate T-cell responses through specific receptor-ligand interactions with B7 family members (5). PD-1 normally acts as an inhibitor of T-cell function (18), and indeed, in mice with chronic LCMV infection, monoclonal antibody blockade of the PD-1-PD-1 ligand interaction reversed functional exhaustion and reduced viral load (5). Likewise, chronic uncontrolled infection with human immunodeficiency virus (HIV) or hepatitis B (HBV) or C (HCV) viruses in humans can lead to functional impairment of the virus-specific CD8⁺ T cells, again marked by their increased PD-1 expression (8, 13, 27, 28, 30, 38, 39).Human herpesviruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), also elicit strong CD8⁺ T-cell responses to virus replicative (lytic) cycle proteins (21, 37), especially during primary infection when they are manifest as infectious mononucleosis (IM) (20, 45). These viruses are never cleared but persist by establishing niches of latent infection, thus evading CD8⁺ T-cell surveillance rather than compromising its function. Occasional low-level reactivations from latency into the lytic cycle provide recurrent antigen challenge and, as a result, the full range of virus-specific CD8⁺ T-cell responses tend to be maintained in the immunocompetent host throughout long-term virus carriage. Interestingly, recent prospective studies of EBV-positive IM patients provided a rare exception to the general stability of herpesvirus-specific CD8⁺ T-cell memory in virus carriers (19). Thus, all HLA-A*0201-positive patients make a primary response to three A*0201-restricted EBV epitopes, YVLDHLIVV, GLCTLVAML, and TLDYKPLSV (designated YVL, GLC, and TLD, respectively). These are derived from three viral proteins, BRLF1, BMLF1, and BMRF1, respectively, that are expressed in the immediate early (BRLF1) and early (BMLF1 and BMRF1) phases of the virus replicative cycle. While YVL- and GLC-specific cells persist in the longer term, as do responses to many other EBV lytic and latent cycle epitopes studied (11, 21, 46), the TLD response almost always disappears (19). Here, we followed the TLD-specific cell population over time post-IM and found that its disappearance is preceded by distinctive changes in the expression of two key markers associated with T-cell fate, IL-7Rα and PD-1.