Different Natural Killer (NK) Cell Subsets Elicit Unique Target Induced Immune Responses: Implications for Assessment of Posttransplant Functional Recovery of the Relevant NK Cell Subsets and Their Impact On HCT Outcomes

BACKGROUND: A normal, fully reconstituted immune system after hematopoeitc cell transplantation (HCT) is critical for the control of post-transplant infections, establishment of graft tolerance and, in some cases, mediation of graft-versus leukemia effects. Natural Killer (NK) cells, being the first in line of defense against tumors and infections, are also the earliest among lymphocyte populations to reconstitute and achieve functional maturity after transplantation. However, many HCT recipients with normal recovery of NK cells continue to suffer from complications including infections and disease relapse suggesting that different NK cell subsets may be responsible for anti-leukemic or anti-viral immune response. Here, we set out to determine in healthy individuals, whether different NK cell subsets (cytolytic or regulatory) elicit unique immune responses against different targets (leukemia cells or herpes viruses).

METHODS: Peripheral Blood Mononuclear Cells (PBMNCs) from 25 healthy donors were stimulated with different targets including a leukemic cell line (K562) and herpesviral (Epstein - Barr virus, EBV) infected cell lysate. A 5-colour flow cytometry based estimation of cytotoxicity (expression of CD107a, a surrogate marker for degranulation) and cytokine (IFN-γ) production was performed for both CD56^brightCD16^neg regulatory and CD56^dimCD16^pos cytolytic NK cell subsets.

RESULTS: Different NK cell subsets were immunodominant against different targets. Leukemia (K562) – specific response includes both degranuation and IFN-γ production mediated by the cytolytic and regulatory NK cell subsets. On the contrary, EBV specific NK cell response was primarily characterized by degranulation and was dominated by cytolytic NK cells. A consistent shedding of CD16 was found associated with degranulation of cytolytic NK cells in response to EBV but not to K562 cells. Cytolytic NK cells in general exhibited a bifunctional immune response against both targets while regulatory NK cells were primarily IFN-γ producers.

CONCLUSIONS: NK cell subsets elicit a unique immune response against different targets (leukemia cells or herpesviruses). Assessment of posttransplant recovery of these target specific functional NK cell subsets will be more relevant for the prediction of transplant outcomes and may have future implications for the cellular therapy/prophylaxis of herpesviral disease or leukemia relapse.