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

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: CD69+CD103+CD8+ TRM 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 CD56dim and CD56bright natural killer cells likewise expressing CD69 and CD103, the latter significantly enriched in renal tumor tissues. CD8+ TRM cell frequencies were not elevated in kidney tumor tissue, but they coexpressed PD-1 and TOX and produced granzyme B. Tumor-derived CD8+ TRM cells from patients with metastases were functionally impaired. Both CD69+CD103-CD4+ and CD69+CD103-CD8+ TRM 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 TRM cells' phenotypes and functions in the human kidney for the first time, pointing toward their potential relevance in kidney transplantation and kidney disease.

The TL1A-DR3 Axis Selectively Drives Effector Functions in Human MAIT Cells.

Mucosal-associated invariant T (MAIT) cells are semi-invariant T cells specifically recognizing riboflavin derivatives that are synthesized by many bacteria and fungi presented by MHC class I-related MR1 molecules. Accumulating evidence, however, indicates that MAIT cell functions are inducible by cytokine stimuli in the absence of TCR ligation, identifying MAIT cells as innate sentinels in inflammatory environments. In this study, we demonstrate that death receptor 3 (DR3), a member of the TNFR superfamily, is ex vivo expressed and predominantly upregulated on the surface of human MAIT cells by innate cytokine stimulation. In turn, the DR3 ligand TNF-like protein 1A (TL1A) licenses innate TNF-α production in the absence of cognate triggers, being sufficient to promote activation of primary endothelial cells in vitro. TL1A further amplifies synthesis of IFN-γ and granzyme B in the presence of otherwise weak innate stimuli and strongly augments polyfunctionality. Mechanistically, TL1A potentiates T-bet expression, early NF-κB, and late p38 MAP kinase phosphorylation, with the latter being indispensable for TNF-α production by MAIT cells. Of note, endogenous TL1A is also rapidly released from PBMC cultures in response to bacterial triggering, thereby equally augmenting Ag-specific MAIT cell effector functions. In summary, to our knowledge, we identify a new inflammatory mechanism in MAIT cells linking the DR3/TL1A axis with amplification of TCR-dependent and -independent effector functions, particularly inducing excessive innate TNF-α production. Given that both TL1A and TNF-α are abundantly present at sites of chronic inflammation, the contribution of MAIT cells in such scenarios needs to be determined.