Signatures and Specificity of Tissue-Resident Lymphocytes Identified in Human Renal Peritumor and Tumor Tissue

Abstract

Background: Tissue-resident memory T (T_RM) 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 T_RM 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: CD69⁺CD103⁺CD8⁺ T_RM cells in kidneys display an inflammatory profile reflected by enhanced IL-2, IL-17, and TNFα production, and their frequencies correlate with increasing age and kidney function. We further identified mucosa-associated invariant T and CD56^dim and CD56^bright natural killer cells likewise expressing CD69 and CD103, the latter significantly enriched in renal tumor tissues. CD8⁺ T_RM cell frequencies were not elevated in kidney tumor tissue, but they coexpressed PD-1 and TOX and produced granzyme B. Tumor-derived CD8⁺ T_RM cells from patients with metastases were functionally impaired. Both CD69⁺CD103^-CD4⁺ and CD69⁺CD103^-CD8⁺ T_RM cells form distinct clusters in tumor tissues in proximity to antigen-presenting cells. Finally, EBV, CMV, BKV, and influenza antigen-specific CD8⁺ T cells were enriched in the effector memory T cell population in the kidney.

Conclusions: Our data provide an extensive overview of T_RM cells' phenotypes and functions in the human kidney for the first time, pointing toward their potential relevance in kidney transplantation and kidney disease.

Keywords: antigen specific; immunology; memory; renal carcinoma; tissue-resident T cells.