ROTRF Recognition Prize – Recognising Excellence in Organ Transplantation Research

13:10: Identification of Stress-regulated Antigens Recognized by Gamma-delta T Cells as Potential Clinical Targets against HCMV Infection and Post-transplant Cancers

Dr Julie Déchanet-Merville, CNRS, Bordeaux, France

The role of unconventional T cells in transplantation still remains elusive. T lymphocytes expressing gamma-delta T cell receptors are unconventional T lymphocytes contributing to immunity against infections and tumors through sensing conserved cellular stress-induced signals and antigens whose nature remains in most instance ignored. We have shown more than ten years ago that one hallmark of organ transplant recipients undergoing human cytomegalovirus (HCMV) infection is a sustained peripheral blood expansion of gamma-delta T cells. We extended these observations to healthy donors, by showing a tight correlation between HCMV seropositivity and gamma-delta T cell percentage/memory phenotype. This close relationship between gamma-delta T cell expansion and HCMV-infection has recently been confirmed by others in diverse pathophysiological contexts. Expansion of gamma-delta T cells in the blood of transplant patients strikingly correlates with both HCMV-infection resolution and decreased cancer risk. Accordingly, gamma-delta T cell clones derived from HCMV-seropositive patients show dual T cell receptor (TCR)-dependent cytotoxic reactivity towards HCMV-infected target cells and several epithelial tumors, suggesting recognition of endogenous stress-induced ligands rather than virus-specific compounds.

We undertook to identify these stress antigens, which may prove interesting targets for clinical manipulation. To this purpose, we generated reporter cell lines expressing gamma-delta TCRs isolated from HCMV-induced gamma-delta T clones in order to select monoclonal antibodies (mAbs) directed against HCMV-infected and tumor targets that are able to block gamma-delta TCR-mediated recognition of target cells. One such transfectant, expressing the Vγ4Vδ5 TCR of the clone LES which represented 25% of T cells in the CMV-infected liver transplant recipient, recently led us to identify endothelial protein C receptor (EPCR) as a novel gamma-delta TCR ligand. LES TCR-dependent reactivity toward HCMV-infected and tumor cells was blocked by anti-EPCR antibodies. Specific direct binding of the recombinant LES TCR to soluble EPCR was ascertained with surface plasmon resonance. EPCR is a class I MHC-like molecule that binds phospholipids analogously to CD1d. EPCR has no previously recognized immunological function, but is known to inhibit coagulation by binding activated protein C, and is implicated in endothelial barrier function. EPCR is expressed on endothelial cells, which are key target of HCMV infection, and is conspicuously upregulated on epithelial tumors, most especially during development of chemotherapy drug resistance. Interestingly enough, EPCR expression was necessary but not sufficient for LES TCR-mediated recognition, raising the possibility that EPCR is a novel presenting molecule of stress-associated lipids for some gamma-delta T cells, consistent with the striking homology between EPCR and CD1d.

These data reveal the human CD1-like molecule EPCR as a novel stress-regulated gamma-delta TCR-ligand offering a revised framework for understanding human lymphoid stress surveillance and opening new perspectives for gamma-delta T cell clinical manipulation in transplant recipients. Along this line, studies are in process in transplant patients to (i) evaluate EPCR as a new presenting molecule of HCMV infection- or cell transformation-related lipid antigens, (ii) localize and characterize the putative in vivo gamma-delta T cell subset restricted by EPCR, (iii) assess the regulation of EPCR expression by HCMV infection in vivo, and (iv) identify other stress-induced antigens recognized by different subset of HCMV-induced gamma-delta T cells.

Julie Déchanet-Merville

Dr Julie Dechanet-Merville received her PhD in Immunology from the University of Lyon (France) in 1995. There, she studied the final stages of B lymphocyte differentiation in the Schering-Plough laboratory for Immunological Research directed by Dr. Jacques Banchereau. She then gained experience in the field of human transplantation immunology during a fellowship in the team of Prof. Jean-Francois Moreau at Bordeaux University. She was recruited as junior scientist by the CNRS in 1998 and settled a research group focused on the implication of DC-SIGN and of human gamma-delta T cells in the host response to cytomegalovirus infection. Many of her studies have involved close and long-lasting interactions with the clinical transplantation department of Bordeaux University Hospital and collaborations with academic partners at the national and international levels. Dr. Dechanet-Merville currently heads a CNRS research team (approximately 25 staff members) at Bordeaux University and her research focuses on the function of human epithelial gamma-delta T lymphocytes in the context of organ transplantation, viral infections and carcinomas. Her studies range from the molecular analysis of gamma-delta T cell antigens to the development of pre-clinical mouse models and the investigation of patient cohorts. She co-authored more than 50 publications on human immunology. She is involved in teaching basic science and lecturing medical students and post-doctoral fellows on human immunology. She reviews papers for several international immunology journals and European medical research organizations.