Introduction: EBV infection elicits a robust host immune response in healthy, immunocompetant individuals. EBV immunity is essential for preventing EBV­-associated lymphomas in transplant recipients, including post­-transplant lymphoproliferative disorder (PTLD). Natural killer (NK) cells are phenotypically heterogeneous lymphocytes capable of responding to viral infection and are known to participate in control of primary EBV infection, when the virus is in a lytic cycle phase. In contrast, the role of NK cells in the immune response to latently-infected B cells, as is seen in EBV+ PTLD, has not been established.

Methods: EBV⁺ lymphoblastoid cell lines (LCL), a model of EBV⁺ B cell lymphomas, were generated in vitro from a cohort of healthy donors (n=11). IL-2-primed primary human NK cells were co-­cultured with primary, normal B cells or autologous EBV⁺ LCLs. Co-cultures were assayed by flow cytometry for target cell cytotoxicity or the functional markers CD107a and IFN-γ, the NK cell marker CD56, the NK maturation marker CD57, and the NK cell receptors NKG2A, NKG2C, NKG2D, 2B4, and CD16.

Results: NK cells were able to induce greater target cell killing of autologous EBV⁺ LCLs than uninfected B cells (8±2.1% vs 2.8±0.6%, p=0.016). In response to the autologous EBV⁺ LCL, 4.1±2% of NK cells produced IFN-γ, 13.5±6% degranulated, and 2.6±1.2% of NK cells both degranulated and produced IFN-γ above background levels. Individual and combinatorial analysis revealed that a higher percent of EBV-specific responding NK cells are NKG2A⁺ and display a 2B4⁺CD16^–CD57^–NKG2A⁺NKG2C⁺NKG2D⁺phenotype.

Conclusion: EBV-specific NK cells constitute an NK cell subset that expresses 2B4⁺CD16^–CD57^–NKG2A⁺NKG2C^–NKG2D⁺. More broadly, these data indicate that NK cells can respond to latently–infected EBV⁺ B cells. Further characterization of this NK cell subset in the response to EBV may provide the basic biological framework to advance innovative, mechanism-based NK cell immunotherapies for EBV⁺ B cell lymphomas that arise after solid organ and bone-marrow transplantation.

CITATION INFORMATION: Hatton O, Strauss-Albee D, Krams S, Blish C, Martinez O. NKG2A-Expressing Natural Killer Cells Dominate the Response to Latent Epstein-Barr Virus Infection. Am J Transplant. 2016;16 (suppl 3).

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