Signatures and specificity of tissue-resident lymphocytes identified in human renal peritumor and tumor tissue

Abstract

Background Tissue-resident memory T (TRM) cells are known to be important for the first line of defense in mucosa-associated tissues. However, the composition, localization, effector function, and specificity of TRM cells in the human kidney and their relevance for renal pathology have not been investigated. Methods Lymphocytes derived from blood, renal peritumor samples, and tumor samples were phenotypically and functionally assessed by applying flow cytometry and highly advanced histology (multi-epitope ligand cartography) methods. Results CD691CD1031CD81 TRM cells in kidneys display an inflammatory profile reflected by enhanced IL-2, IL- 17, andTNFa production, andtheir frequencies correlatewith increasingage andkidney function.We further identified mucosa-associated invariant T and CD56dim and CD56bright natural killer cells likewise expressing CD69 and CD103, the latter significantly enriched in renal tumor tissues. CD81 TRM cell frequencieswere not elevated in kidney tumor tissue, but they coexpressed PD-1 and TOX and produced granzyme B. Tumor-derived CD81 TRM cells from patients withmetastases were functionally impaired. Both CD691CD1032CD41 and CD691CD1032CD81 TRM cells formdistinct clusters in tumor tissues inproximity toantigen-presentingcells.Finally,EBV,CMV,BKV, and influenza antigen-specific CD81 T cells were enriched in the effector memory T cell population in the kidney. Conclusions Our data provide an extensive overviewof TRM cells' phenotypes and functions in the human kidney for the first time, pointing toward their potential relevance in kidney transplantation and kidney disease.