EBV-Specific CD8+ T Cells from Asymptomatic Pediatric Thoracic Transplant Patients Carrying Chronic High EBV Loads Display Contrasting Features: Activated Phenotype and Exhausted Function

Abstract

Serial EBV load monitoring of clinically asymptomatic pediatric thoracic organ transplant patients has identified three groups of children who exhibit undetectable (<100 copies/ml), chronic low (100-16,000 copies/ml), or chronic high (>16,000 copies/ml) EBV loads in peripheral blood. Chronic high EBV load patients have a 45% rate of progression to late-onset posttransplant lymphoproliferative disorders. In this article, we report that asymptomatic patients carrying EBV loads (low and high) expressed increased frequencies of EBV-specific CD8(+) T cells, as compared with patients with undetectable EBV loads. Although patients with low viral load displayed EBV-specific CD8(+) T cells with moderate signs of activation (CD38(+/-)/CD127(+/-)), programmed death 1 upregulation and effective IFN-γ secretion, high EBV load carriers showed significant CD38(+) upregulation, features of cellular exhaustion (programmed death 1(+)/CD127(-)) accompanied by a decline in IFN-γ release. Immunopolarization of EBV-specific CD8(+) T cells was skewed from the expected type 1 (IFN-γ) toward type 0 (IFN-γ/IL-5) in patients, and Tr1 (IL-10) in high load carriers. These results indicate the importance of chronic EBV load and of the levels of antigenic pressure in shaping EBV-specific memory CD8(+) T cells. Concomitant phenotypic and functional EBV monitoring is critical for identifying the complex "functional" versus "exhausted" signature of EBV-specific CD8(+) T cells, with implications for immunologic monitoring in the clinic.