Annette Fink

Heidelberg University

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Claudia Tritschler

University of Pennsylvania

Matthias J. Reddehase

Johannes Gutenberg University Mainz

Niels A. W. Lemmermann

University of Bonn

Jürgen Podlech

Johannes Gutenberg University Mainz

Rafaela Holtappels

Johannes Gutenberg University Mainz

Thuong Hien Tran

University Hospital Heidelberg

Julia K. Büttner

University Medical Center of the Johannes Gutenberg University Mainz

Caner Süsal

Heidelberg University

Stefan Ebert

University Medical Center of the Johannes Gutenberg University Mainz

Sara Becker

University Hospital Bonn

Cooperative Institutions

Heidelberg University

University Hospital Heidelberg

Johannes Gutenberg University Mainz

German Cancer Research Center

University Medical Center of the Johannes Gutenberg University Mainz

Deutschen Konsortium für Translationale Krebsforschung

Heinrich Heine University Düsseldorf

RWTH Aachen University

Düsseldorf University Hospital

Ludwig-Maximilians-Universität München

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Direct Antigen Presentation is the Canonical Pathway of Cytomegalovirus CD8 T-cell Priming Regulated by Balanced Immune Evasion Mounting a Strong Antiviral Response

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Julia K. Büttner Sara Becker Annette Fink Melanie M. Brinkmann Rafaela Holtappels

Abstract CD8 T cells are the main antiviral effectors of the adaptive immune response to cytomegaloviruses (CMVs) in confining acute infection and in long-term surveillance of latent infection. An unresolved issue of debate, with diametrically opposite conclusions, is the mechanism by which CMV-specific naïve CD8 T cells are primed. The idea of priming by antigen cross-presentation through uninfected professional antigen presenting cells taking up viral proteins derived from infected cells was based on the observation that the net response is not improved when direct presentation is enhanced by deletion of viral ‘immune evasion’ genes affecting the classical MHC class-I pathway of antigen presentation. Redundance of priming mechanisms has been demonstrated by experimental models in which either pathway has been rendered inaccessible, so that both pathways are, in principle, capable of priming CD8 T cells. For studying CMV-specific priming in the normal host competent in both antigen presentation pathways, we took the novel approach to enhance instead of delete immune evasion protein expression. Surprisingly, the net magnitude of the CD8 T-cell response in the regional lymph node draining a local site of infection was identical for the contrasts of reduced or enhanced direct antigen presentation. At first glance, this may lead one to conclude that direct presentation plays no role in priming. This interpretation, however, is incompatible with the finding that an intermediate extent of direct antigen presentation, as it exists for wild-type virus, resulted in the best CD8 T-cell response. Our findings thus revealed an essential positive role of a balanced viral immune evasion in mounting a strong antiviral immune response. This novel insight sheds a completely new light on the acquisition of viral immune evasion genes during virus-host co-evolution.

Priming (agriculture)

Cross-Presentation

Antigen processing

10.1101/2023.09.01.555841

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Donor-Derived Cell-Free DNA (dd-cfDNA) in Kidney Transplant Recipients With Indication Biopsy—Results of a Prospective Single-Center Trial

Transplant International (2023)

Louise Benning Christian Morath Annette Fink Markus Rudek Claudius Speer

Donor-derived cell-free DNA (dd-cfDNA) identifies allograft injury and discriminates active rejection from no rejection. In this prospective study, 106 kidney transplant recipients with 108 clinically indicated biopsies were enrolled at Heidelberg University Hospital between November 2020 and December 2022 to validate the clinical value of dd-cfDNA in a cohort of German patients. dd-cfDNA was quantified at biopsy and correlated to histopathology. Additionally, dd-cfDNA was determined on days 7, 30, and 90 post-biopsy and analyzed for potential use to monitor response to anti-rejection treatment. dd-cfDNA levels were with a median (IQR) % of 2.00 (0.48–3.20) highest in patients with ABMR, followed by 0.92 (0.19–11.25) in patients with TCMR, 0.44 (0.20–1.10) in patients with borderline changes and 0.20 (0.11–0.53) in patients with no signs of rejection. The AUC for dd-cfDNA to discriminate any type of rejection including borderline changes from no rejection was at 0.72 (95% CI 0.62–0.83). In patients receiving anti-rejection treatment, dd-cfDNA levels significantly decreased during the 7, 30, and 90 days follow-up compared to levels at the time of biopsy ( p = 0.006, p = 0.002, and p < 0.001, respectively). In conclusion, dd-cfDNA significantly discriminates active rejection from no rejection. Decreasing dd-cfDNA following anti-rejection treatment may indicate response to therapy. Clinical Trial Registration : https://drks.de/search/de/trial/DRKS00023604 , identifier DRKS00023604.

Cell-free fetal DNA

Nephrology

Single Center

Histopathology

10.3389/ti.2023.11899

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Citations (8)

Donor-Derived Cell-Free DNA (dd-cfDNA) in Kidney Transplant Recipients With Indication Biopsy: Results of a Prospective Single-Center Trial

Journal of the American Society of Nephrology (2022)

Louise Benning Annette Fink Florian Kälble Claudius Speer Christian Nußhag

Single Center

Cell-free fetal DNA