title: Clinically Relevant Reactivation of Polyomavirus BK (BKPyV) in HLA-A02-Positive Renal Transplant Recipients Is Associated with Impaired Effector-Memory Differentiation of BKPyV-Specific CD8+ T Cells.
abstract: Polyomavirus BK (BKPyV) frequently reactivates in immunosuppressed renal transplant recipients (RTRs) and may lead to graft loss due to BKPyV-induced interstitial nephritis (BKVN). Little is known on the differentiation of CD8+ T cells targeting BKPyV in RTRs. Here we investigated whether BKPyV-specific CD8+ T cell differentiation differs in RTRs with varying degrees of BKPyV reactivation and/or BKVN. Using combinatorial encoding with tetramers carrying BKPyV major capsid protein (VP1) and large T antigen protein (LTAG) epitopes, we investigated CD8+ T cell responses to BKPyV in longitudinally obtained PBMC samples from 46 HLA-A02-positive RTRs and 20 healthy adults. We were also able to isolate BKPyV-specific CD8+ T cells from five renal allografts, two of which were affected by BKVN. Before transplantation, BKPyV-specific CD8+ T cells targeting VP1 and LTAG epitopes appeared predominantly as central-memory and CD27+/CD28+ effector-memory (TEM), and naïve-like PD-1-expressing cells, respectively. After viral reactivation, BKPyV-specific CD8+ T cells assumed CD28- TEM and TEMRA states in patients who were able to control BKPyV, whereas differentiation lagged behind in patients with severe viral reactivation or BKVN. Furthermore, VP1-specific CD69+/CD103+ tissue-resident memory (TRM) cells accumulated in BKVN-affected allografts but lacked signs of effector differentiation. In contrast, granzyme B-expressing effector cells were detected in allografts not affected by BKVN. In conclusion, effector-memory differentiation of BKPyV-specific CD8+ T cells in patients with high viral load or BKVN is impaired. Further characterization of the specific mechanisms behind this altered cellular differentiation is necessary to develop therapies that can prevent the emergence of BKVN.
authors.affiliation: Department of Experimental Immunology, Amsterdam, the Netherlands.|Renal Transplant Unit, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Michiel C
authors.identifier: http://orcid.org/0000-0003-3379-8306
authors.initials: MC
authors.lastname: van Aalderen
authors.affiliation: Department of Experimental Immunology, Amsterdam, the Netherlands.|Renal Transplant Unit, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Ester B M
authors.initials: EB
authors.lastname: Remmerswaal
authors.affiliation: Department of Experimental Immunology, Amsterdam, the Netherlands.|Renal Transplant Unit, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Kirstin M
authors.initials: KM
authors.lastname: Heutinck
authors.affiliation: Sanquin Blood Supply Foundation and Landsteiner laboratory, Amsterdam, the Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Ten Brinke
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Mariet C W
authors.initials: MC
authors.lastname: Feltkamp
authors.affiliation: Renal Transplant Unit, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Neelke C
authors.initials: NC
authors.lastname: van der Weerd
authors.affiliation: Renal Transplant Unit, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Karlijn A M I
authors.initials: KA
authors.lastname: van der Pant
authors.affiliation: Renal Transplant Unit, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Frederike J
authors.initials: FJ
authors.lastname: Bemelman
authors.affiliation: Sanquin Blood Supply Foundation and Landsteiner laboratory, Amsterdam, the Netherlands.
authors.forename: René A W
authors.initials: RA
authors.lastname: van Lier
authors.affiliation: Department of Experimental Immunology, Amsterdam, the Netherlands.|Renal Transplant Unit, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Ineke J M
authors.initials: IJ
authors.lastname: Ten Berge
mesh_terms: D000328:Adult; D001739:BK Virus; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015789:HLA-A2 Antigen; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology; D007156:Immunologic Memory; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections / Q000276:immunology*; D066027:Transplant Recipients; D014412:Tumor Virus Infections / Q000276:immunology*; D014775:Virus Activation / Q000276:immunology*
chemical_list: C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen