Rationale: Cytomegalovirus (CMV), which is one of the most common infections after lung transplantation, is associated with chronic lung allograft dysfunction and worse post-transplantation survival. Current approaches for at-risk patients include a fixed duration of antiviral prophylaxis despite the associated cost and side effects.

Objectives: We sought to identify a specific immunologic signature that predicted protection from subsequent CMV.

Methods: CMV-seropositive lung transplantation recipients were included in the discovery (n = 43) and validation (n = 28) cohorts. Polyfunctional CMV-specific immunity was assessed by stimulating peripheral blood mononuclear cells with CMV pp65 or IE-1 peptide pools and then by measuring T-cell expression of CD107a, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2. Recipients were prospectively monitored for subsequent viremia. A Cox proportional hazards regression model that considered cytokine responses individually and in combination was used to create a predictive model for protection from CMV reactivation. This model was then applied to the validation cohort.

Measurements and Main Results: Using the discovery cohort, we identified a specific combination of polyfunctional T-cell subsets to pp65 that predicted protection from subsequent CMV viremia (concordance index 0.88 [SE, 0.087]). The model included both protective (CD107a⁻/IFN-γ⁺/IL-2⁺/TNF-α⁺ CD4⁺ T cells, CD107a⁻/IFN-γ⁺/IL-2⁺/TNF-α⁺ CD8⁺ T cells) and detrimental (CD107a⁺/IFN-γ⁺/IL-2⁻/TNF-α⁻ CD8⁺ T cells) subsets. The model was robust in the validation cohort (concordance index 0.81 [SE, 0.103]).

Conclusions: We identified and validated a specific T-cell polyfunctional response to CMV antigen stimulation that provides a clinically useful prediction of subsequent cytomegalovirus risk. This novel diagnostic approach could inform the optimal duration of individual prophylaxis.