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A recent research breakthrough on communication between B cells infected with Epstein Barr Virus (EBV) and natural killer T (NKT) cells may pave the way to a vaccine for EBV. EBV is a ubiquitous human Herpes virus and can persist sub-clinically for life. It mainly infects B cells and is combated by cytotoxic T cells and by NK cells. EBV infection is linked to mononucleosis, Hodgkin's lymphoma and nasopharyngeal carcinoma. It is perhaps most devastating in immunocompromised hosts, being associated with haemophagocytic lymphohistiocytosis (HLH) and lymphoproliferative diseases with some types of primary immunodeficiencies having EBV-associated complications as their predominant clinical feature.

NKT cells (or Type I NKT cells) are a heterogeneous group of T cells that have properties in common both with cytotoxic T cells and natural killer (NK) cells, which are the main cytotoxic cell of the innate immune system and target virally infected cells and tumour cells. iNKT cells express an invariant Valpha14 T cell receptor and are restricted to the CD1d ligand. Their development is dependent on the signalling lymphocytic activation molecule (SLAM)-associated protein (SAP), which is encoded by the SH2D1A gene on the X chromosome. SH2D1A gene mutation or deletion has been identified as the genetic basis of X-linked lymphoproliferative disease (XLP). Individuals who suffer from X-linked XLP lack invariant natural killer T (iNKT) cells and are highly susceptible to EBV infection. This susceptibility helped give researchers in the University of British Columbia and British Columbia’s Children’s Hospital in Vancouver in Canada a clue as to how EBV may evade the immune system and how it could be targeted for destruction (Chung et al. 2013).

The researchers found that if resting B cells were infected with EBV in the absence of iNKT cells, both viral titres and the frequency of EBV-infected B cells were increased when compared to B cells in the presence of iNKT cells. However, even in the presence of iNKT cells, the infected B cells were observed to rapidly lose expression of the iNKT ligand CD1d, which attenuated the iNKT response. In order to determine if the iNKT responsiveness could be restored by up-regulation of CD1d in infected B cells, the researchers treated EBV-infected lymphoblastoid cell lines (LCL) with AM580, a synthetic retinoic acid receptor-α (RARα) agonist that up-regulates CD1d expression. This CD1d up-regulation restored iNKT recognition of LCL even in the absence of exogenous antigen which suggests that an endogenous iNKT antigen is expressed during EBV infection. Thus it appears that even in hosts which have iNKT cells, the EBV infection causes down-regulation of CD1d and enables the virus to escape iNKT-mediated immune recognition. The researchers' hope is that if the infected cells can be ‘forced’ to express CD1d, then iNKT recognition will be restored and the basis of a vaccine will be laid, thus bringing new hope particularly to immunocompromised individuals.

Sources
CHUNG, B.K. et al., 2013. Innate immune control of EBV-infected B cells by invariant natural killer T cells. American Society of Hematology.

FURUKAWA, H. et al., 2010. Role of SLAM-associated protein in the pathogenesis of autoimmune diseases and immunological disorders. Archivum Immunologiae et Therapiae Experimentalis, 58(1), pp. 37-44

NAGY, N. and KLEIN, E., 2010. Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development. Immunology letters, 130(1-2), pp. 13-18

PARVANEH, N., FILIPOVICH, A.H. and BORKHARDT, A., 2013. Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases. British journal of haematology, 162(5), pp. 573-586

Child & Family Research Institute. "Immune system discovery could lead to vaccine to prevent mono, some cancers." ScienceDaily, 12 Oct. 2013. Accessed 14 Oct. 2013.