The importance of cellular metabolism for the functionality of virus-specific CD8+ T cells in kidney transplant recipients.

• Applicant: Dr. Nils Mülling
• Subject Area: Nephrology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 526085745

Viral infections are of great clinical relevance in kidney transplant patients. Cytomegalovirus infection is one of the most common opportunistic infections in this patient group and is associated with significantly worse graft function even in the case of asymptomatic viral replication. CD8+ T cells are of outstanding relevance to fight viral infections. The induction of virus-specific CD8+ T cells can be achieved by either infection or vaccines. Based on this, CMV-specific as well as vaccine-induced SARS-CoV-2-specific CD8+ T cells will be considered in this project. Despite intensive research in the field of CMV infection in immunosuppressed individuals, it is still not clear which immunological component is crucial for good CMV control. However, it is increasingly assumed that not so much the quantitative but rather the qualitative properties of CMV-specific immune cells play an important role. Based on this assumption, this project will focus on the metabolism of CMV-specific CD8+ T cells, which has been poorly studied to date. In addition, an intraindividual comparison with SARS-CoV-2-specific T cells, which are not subject to chronic antigen stimulation, will be performed. In the first part of the project, T cell metabolic alterations associated with poor viral control of kidney transplant patients will be identified. In the second part of the project, the functionality of these T cells will be improved by optimizing their metabolism. In order to multidimensionally analyze virus-specific CD8+ T cell immunity at the single cell level, studies on the transcriptional level, protein expression as well as functional assays will be used. In addition to a broader analysis of metabolism by RNA sequencing, the uptake and metabolism of glucose, lipids and amino acids as well as mitochondrial metabolism will be specifically investigated. It is well known that kidney transplant patients are frequently exposed to metabolic pathologies such as malnutrition, dyslipidemia, hypo- or hyperglycemia, but also chronic inflammation. Therefore, we will investigate how virus-specific T cells can respond to the different availability of nutrients and an artificially generated inflammatory milieu by maintaining their functionality. In addition, we will try to improve the proliferation and cytokine secretion capacity of virus-specific t cells by optimizing mitochondrial functionality, e.g. by adding mitochondrial antioxidants. The knowledge gained from this project may support new approaches in which T cell metabolism is used as a therapeutic target to combat viral infections.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Participating Institution: University Leiden Medical Center; Department of Immunology
• Host: Dr. Ramon Arens