title: HLA-E-restricted cross-recognition of allogeneic endothelial cells by CMV-associated CD8 T cells: a potential risk factor following transplantation.
abstract: Although association between CMV infection and allograft rejection is well admitted, the precise mechanisms involved remain uncertain. Here, we report the characterization of an alloreactive HLA-E-restricted CD8 T cell population that was detected in the PBL of a kidney transplant patient after its CMV conversion. This monoclonal CD8 T cell population represents a sizable fraction in the blood (3% of PBL) and is characterized by an effector-memory phenotype and the expression of multiple NK receptors. Interestingly, these unconventional T cells display HLA-E-dependent reactivity against peptides derived from the leader sequences of both various HCMV-UL40 and allogeneic classical HLA-I molecules. Consequently, while HLA-E-restricted CD8 T cells have potential to contribute to the control of CMV infection in vivo, they may also directly mediate graft rejection through recognition of peptides derived from allogeneic HLA-I molecules on graft cells. Therefore, as HLA-E expression in nonlymphoid organs is mainly restricted to endothelial cells, we investigated the reactivity of this HLA-E-restricted T cell population towards allogeneic endothelial cells. We clearly demonstrated that CMV-associated HLA-E-restricted T cells efficiently recognized and killed allogeneic endothelial cells in vitro. Moreover, our data indicate that this alloreactivity is tightly regulated by NK receptors, especially by inhibitory KIR2DL2 that strongly prevents TCR-induced activation through recognition of HLA-C molecules. Hence, a better evaluation of the role of CMV-associated HLA-E-restricted T cells in transplantation and of the impact of HLA-genotype, especially HLA-C, on their alloreactivity may determine whether they indeed represent a risk factor following organ transplantation.
authors.affiliation: Inserm, U892, Nantes, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Allard
authors.forename: Pierre
authors.initials: P
authors.lastname: Tonnerre
authors.forename: Steven
authors.initials: S
authors.lastname: Nedellec
authors.forename: Romain
authors.initials: R
authors.lastname: Oger
authors.forename: Alexis
authors.initials: A
authors.lastname: Morice
authors.forename: Yannick
authors.initials: Y
authors.lastname: Guilloux
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Houssaint
authors.forename: Béatrice
authors.initials: B
authors.lastname: Charreau
authors.forename: Nadine
authors.initials: N
authors.lastname: Gervois
mesh_terms: D001158:Arteries / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002469:Cell Separation; D003429:Cross Reactions / Q000187:drug effects / Q000276:immunology*; D003587:Cytomegalovirus / Q000187:drug effects / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016030:Kidney Transplantation; D010641:Phenotype; D021382:Protein Sorting Signals; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D055607:Receptors, Natural Killer Cell / Q000276:immunology; D012307:Risk Factors; D014184:Transplantation, Homologous
chemical_list: D006680:HLA Antigens; D021382:Protein Sorting Signals; D011948:Receptors, Antigen, T-Cell; D055607:Receptors, Natural Killer Cell; D007371:Interferon-gamma