Melbourne research aims to show how Epstein is barred

Researchers from Monash and Melbourne Universities investigating the immune response toward the Epstein-Barr virus (EBV) have used crystallographic techniques to visualise the shape of the T-cell receptor that specifically prevents the virus from wreaking havoc.

Around 90 per cent of people are infected with EBV, a herpes virus that causes a chronic or persistent infection. In most people this is not a problem and the virus remains latent, but in immunosuppressed individuals, the virus activates and can be fatal.

The suppression of the virus is under the control of cytotoxic T cells (CTLs), which carry T-cell receptors, similar to antibodies. Each individual has a repertoire of T-cell receptors, varying primarily at the site of interaction with the peptide-MHC complex, and generated by a complex genetic lottery system and selection process to create a pool of around one hundred million unique receptors.

And each T-cell receptor recognises a specific peptide complexed to a protein from the major histocompatibility complex (MHC) protein family, also known as HLA. Each individual has several different MHC molecules, known as HLA-A, HLA-B, and so on.

Unusually, EBV-infected individuals with a particular MHC protein variant, known as HLA-B8, overwhelmingly produce an immunodominant T-cell receptor that is virtually identical in all HLA-B8 individuals, recognising a peptide from EBV latent antigen EBNA 3a in complex with the HLA-B8 protein. This implies that this particular receptor has some advantage over other T-cell receptors that could possibly recognise the peptide-MHC complex.

The researchers, Jamie Rossjohn and Craig Clements from Monash's department of biochemistry and James McCluskey, Lars Kjer-Nielsen, Anthony Purcell and Andrew Brooks from Melbourne University's Department of Immunology, used crystallography to examine the interaction of the T-cell receptor with the peptide-MHC protein complex, and compared it to the structures of the T-cell receptor and the peptide-MHC complexes alone, previously obtained by the same researchers.

The research, published in the latest issue of Immunity, was based on earlier observations made by Queensland Institute of Medical Research scientist Scott Burrows.

They found that the immunodominant T-cell receptor undergoes conformational changes, which somehow enhances the interaction between the T-cell receptor and the peptide-MHC complex, causing preferential selection of the T cell bearing this receptor and possibly some as yet unknown enhancement of the signalling pathways in the cell.

This suggests that the relationship between the virus and the receptor is ancient, and in fact, the HLA-B8 variant is a common one in Caucasian populations indicating that the variant perhaps is advantageous for protection against EBV infection.

But beyond the investigation into the fundamentals of immunology, Rossjohn and his colleagues are also interested in how EBV can cause organ transplant rejection in certain individuals, particularly when an organ of HLA type B44 is donated to an EBV-infected HLA-B8 individual. Around 25 per cent of Caucasians have the HLA-B44 protein.

"The T-cell receptor we have studied interacts with Epstein Barr Virus and stops it from running rampant through the body but, in some transplant patients, the receptor can also interact with molecules in the organ being transplanted and contribute to it being rejected," Rossjohn said.

In these patients, the immunodominant T-cell receptor produced to suppress the EBV infection cross-reacts with certain variants of the HLA-B44 molecule causing a cytotoxic or killer response to be directed toward the transplanted organ, thus causing rejection.

"Now that we know the structure of the T-cell receptor we can also begin to understand the molecular basis for transplant rejection," Rossjohn says.

Rossjohn and his colleagues plan to explore this further, and are looking at the structure of the HLA-B44 protein. Already they have found that a single amino acid can mean the difference between a successful transplant and rejection, says Rossjohn.

"If we can find a general mechanism for immune recognition of foreign tissues then perhaps this can be blocked so that transplants can proceed without fear of rejection," Rossjohn says.