Servicenavigation

Project Details

Back

Projekt Print View

Role of Tissue-Resident Leukocytes in the Kidney – Implications for Allograft Survival According to Age

Subject Area General and Visceral Surgery
Reproductive Medicine, Urology
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 421576852
 
Final Report Year 2023

Final Report Abstract

Originally based on data from murine infection models, the concept of tissue residency states that the majority of immune cells does not circulate in blood and/or lymph, but resides in tissues. Such tissueresident cells are limited in their capacity to re-circulate, show location-specific functional adaptations, thereby providing organ-tailored protection against site-specific pathogens. Whereas features of tissueresident memory T cells (TRM) have been meanwhile extensively examined in murine infection-, tumorand autoimmune-models, only limited data are available with respect to composition, antigen specificities and functions of their human counterparts. On this background, our data contribute to the understanding of how immunological T cell memory is organized in human kidneys: we demonstrate that the pool of renal tissue-resident T cells expands with advancing age and shows functional diversification compared to their blood-derived counterparts. Furthermore, by screening for renal T-cell specificities, we show that the kidney harbors unexpectedly high TRM frequencies specific for seasonal pathogens such as influenza. This result is surprising, given the assumption that tissue residency is acquired by organ- or tissue-specific infections, being not intuitive for the combination of influenza and the non-mucosal organ kidney. Extending our data on lymphocytes from human tissues, we conducted a comprehensive analysis of SARS-CoV2 vaccination induced immunological memory in multiple lymphoid and non-lymphoid organs, including kidney. Vaccine-specific CD4+ T cells could be detected in most peripheral tissues, showing distinct adaptations with respect to memory-phenotype, function and tissue residency signatures in comparison to blood-derived cells. This includes persistence of specific T cells in tissues largely unrelated to donor age, supporting the idea of a protected niche in organs. It remains an open question whether vaccination-induced T cells are primed locally and then migrate to distant organs or whether vaccination antigens are distributed to distant sites such as kidney and liver areas and are primed at more than the vaccine inoculation site. The second hypothesis at least seems principally possible since it has been shown that intramuscularly applied model mRNA antigens in mice could be detected at distant organs such as lung and liver. Data from our experimental murine models suggest that an ageing immune system does not only lead to fundamental changes within the lymphocyte compartment, but includes antigen-presenting cells within the kidney modifying their functional program with respect to increased expression of (co-) stimulatory molecules. Given their important role in T cell activation, this finding is of particular importance in the transplantation setting. Using an innovative strategy to deplete senescent cells in the kidney transplant, we provide evidence that such inflamm-ageing-associated changes in aged organs could be targeted: resulting from pretreatment of the organ-donor with the senolytic drug ABT-263, we found a reduced inflammatory signature within the T- and NK-cell compartment of the kidney transplant, associated with improved long-term function. Taking into account the progressive ageing of the population, by nature paralleled by an increase in aged transplants, we provide an experimental approach to principally expand the donor organ pool.

Publications

 
 

Additional Information

© 2025 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung