CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer

Abstract

CD8⁺ T cells that express retinoic acid-related orphan receptor (ROR)γt (T_C17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8⁺RORγt⁺ T cells (T_C17 cells) was increased in peripheral blood. The CD8⁺RORγt⁺ T cells represented a highly activated subset and produced IL-17A in equal amount as CD4⁺RORγt⁺ T cells (T_H17 cells). Most CD8⁺RORγt⁺ T cells coexpressed T-bet, a lineage transcription factor for T_H1 and T_C1 development, suggesting that CD8⁺RORγt⁺ T cells undergo plasticity toward a T_C17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8⁺RORγt^- T cells, the CD8⁺RORγt⁺ T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8⁺RORγt⁺ T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8⁺RORγt⁺ T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC.