Innate and Adaptive Immune Correlates of Chronic and Self-limiting EBV DNAemia in Solid-organ Transplant Recipients.

BACKGROUND

Epstein-Barr virus (EBV) DNAemia is a major risk factor for posttransplant lymphoproliferative disorder; however, immune correlates of EBV DNAemia in the transplant setting are limited.

METHODS

Peripheral blood mononuclear cells were collected from 30 transplant recipients with self-limiting EBV DNAemia (SLD; n = 11) or chronic EBV DNAemia (CD; n = 19) at enrollment and 4-8 weeks later. Mass cytometry was used to characterize innate and T-cell immune correlates of EBV DNAemia. Furthermore, flow cytometry was used to measure the frequency of EBV-specific T-cell responses between groups following stimulation with an EBV-infected cell lysate.

RESULTS

Unsupervised analysis of the innate compartment (CD3CD19 cells) identified 5 CD11c clusters at higher abundance in the SLD group (false discovery rate ≤ 1%). These clusters expressed CD11b, CD45RO, CD14, CD123, CD127, and CD38, among others. Unsupervised profiling of the T-cell compartment (CD3CD19) revealed 2 CD4 T-cell clusters at higher frequency among those with SLD (false discovery rate ≤ 1%), which expressed CD45RA, CCR7, CD27, CD28, and CD40L-suggestive of a naive T cell (TN). Manual biaxial gating confirmed increased frequencies of conventional dendritic cells (3.1% versus 2.1%; P = 0.023) and CD4 TN (4.4% versus 1.9%; P = 0.018) among those with SLD. Last, frequencies of interferon-γ-producing EBV-specific CD4 T cells were significantly lower in the CD group relative to those with SLD (4243 versus 250 cells/10 cells; P = 0.015).

CONCLUSIONS

CD is associated with a reduction of CD11c cells, CD4 TN, and interferon-γ-producing EBV-specific CD4 T cells, suggesting an interplay between innate and adaptive immune compartments may be important for regulating EBV DNAemia.