Polyfunctional T-Cell Signatures to Predict Protection from Cytomegalovirus after Lung Transplantation

Am J Respir Crit Care Med. 2016 Jan 1;193(1):78-85. doi: 10.1164/rccm.201504-0733OC.


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.

Keywords: cytomegalovirus; immunologic monitoring; lung transplantation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Cytomegalovirus / immunology
  • Cytomegalovirus Infections / etiology
  • Cytomegalovirus Infections / immunology*
  • Female
  • Flow Cytometry
  • Graft Survival / immunology
  • Humans
  • Interferon-gamma / immunology
  • Interleukin-2 / immunology
  • Lung Transplantation / adverse effects*
  • Lysosomal-Associated Membrane Protein 1 / immunology
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Risk Factors
  • T-Lymphocytes / immunology*
  • Tumor Necrosis Factor-alpha / immunology
  • Viremia / immunology


  • Interleukin-2
  • Lysosomal-Associated Membrane Protein 1
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma