NK ALERT! New Subpopulation Linked in Restriction of B-Cell Transformation by EBV

EBV, or Epstein-Barr Virus, is a pretty common and current virus that affects approximately well over ninety percent of the human adult population. The virus belongs to the herpes family meaning after the bodies defenses respond to the initial viral lytic infection, the virus remains latent in B cells till further proliferation. The virus enters our tonsils after initial transmission via the saliva¹.

Usually, in the vast majority of infected individuals, virus induced CD8⁺ T cells are responsible for the main fight against EBV infection. However, Natural Killer (NK) cells play an important role for the initial innate immune response against EBV. This paper, A Distinct Subpopulation of Human NK Cells Restricts B Cell Transformation by EBV, further explores the abilities of a specific subpopulation of NK cells in preventing B cell transformation by EBV. The specific NK subpopulation, known as CD56brightNKG2A+CD94+CD54+CD62L2, was seen by researchers to produce an interestingly high amount of IFN-γ³. IFN-γ is an important cytokine that is essential for innate and adaptive immunity when dealing with viral and intracellular bacterial infections. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly for its immunostimulatory and immunomodulatory effects.³ So what does this mean?

EBV is fairly common, however, there is a small subset of EBV infected individuals who due to certain B and epithelial cell transforming capacity, cause rather serious, detrimental EBV-associated illnesses¹. It is this high interferon gamma producing subpopulation that the researchers want to focus on in order for future development of cell based beneficial approaches to EBV associated illness patients.

The goal of the experiments for the researchers became to see if this specific subpopulation of NK cells truly produces high amounts of IFN-γ, in addition to measuring its activity in restricting B cell transformation, and to determine what about these NK cells make them so superior than others.

To determine the amount of IFN-γ produced by this subpopulation the researchers stimulated the subpopulation of CD56brightNKG2A+CD94+CD54+CD62L2 for eighteen hours with IL-12; this cytokine is an important protein that stimulates NK cells to produce IFN-γ². The experiment showed that the grand majority of cells were all IFN-γ producing cells. To determine the ability of this subpopulation to restrict B cell transformation a B cell regression assay was performed. The assay was carried out by co culturing about a hundred thousand EBV exposed autologous B cells with different types of tonsilar NK cell as well as IL-12. The assay showed that the specific subpopulation aforementioned were 4.5 fold more efficient at preventing the outgrowth of EBV infected B cells¹.

In conclusion, the researchers did a great job focusing in on a specific subpopulation of NK cells that had the incredible phenotype of unusually high IFN-γ production. The experiments performed gave a high amount of confidence that it is this characteristic that identifies the subpopulation. Specifically, this paper could shed light on an interesting new type of therapy, NK cell based transplantation therapies. These therapies have begun to be used by people who have hematological malignancies, such as leukemia, with a high efficiency of residual leukemia clearance after chemotherapy⁴. With such advances in this field, perhaps this paper can lead to a new type of therapy that could implant this certain NK subpopulation, CD56brightNKG2A+CD94+CD54+CD62L2, into EBV- associated individuals.

References:

Primary article:

1.)   Tarik Azzi, Anna Lunemann, Christian Munz, David Nadal, Liliana D. Vanoaica. 2013. A Distinct Subpopulation of Human NK Cells Restricts B Cell Transformation by EBV. Journal of Immunology. 109: 4989-4995.

Other Articles:

2.)   Fehniger, T. A., M. A. Cooper, G. J. Nuovo, M. Cella, F. Facchetti, M. Colonna, and M. A. Caligiuri. 2003. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link be- tween adaptive and innate immunity. Blood 101: 3052–3057.

3.)    Strowig, T., F. Brilot, F. Arrey, G. Bougras, D. Thomas, W. A. Muller, and C. Mu ̈nz. 2008. Tonsilar NK cells restrict B cell transformation by the Epstein- Barr virus via IFN-g. PLoS Pathog. 4: e27.

4.)    Curti, A., L. Ruggeri, A. D’Addio, A. Bontadini, E. Dan, M. R. Motta, S. Trabanelli, V. Giudice, E. Urbani, G. Martinelli, et al. 2011. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118: 3273–3279.