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

• Published in: The Journal of immunology (1950) 2017-02, Vol.198 (4), p.1729-1739
• Main Authors: Chellappa, Stalin, Hugenschmidt, Harald, Hagness, Morten, Subramani, Saranya, Melum, Espen, Line, Pål Dag, Labori, Knut-Jørgen, Wiedswang, Gro, Taskén, Kjetil, Aandahl, Einar Martin
• Format: Article
• Language: English
• Subjects: Aged; Apoptosis; Bile Duct Neoplasms - immunology; Bile Duct Neoplasms - physiopathology; Bile ducts; Cancer; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell death; Cell Differentiation - immunology; Cholangiocarcinoma; Cytotoxicity; Degranulation; Female; Helper cells; Humans; Immune response; Inflammation; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin-17 - biosynthesis; Interleukin-17 - immunology; Lymphocytes; Lymphocytes T; Male; Membrane Glycoproteins - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Pathogenesis; Perforin; Perforin - genetics; Peripheral blood; Phenotype; Programmed Cell Death 1 Receptor - genetics; Receptors, Antigen, T-Cell - metabolism; Retinoic acid; Survival Analysis; T cell receptors; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Th17 Cells - immunology; Tumor necrosis factor; Tumor Necrosis Factors - genetics; Tumors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600061

CD8 T cells that express retinoic acid-related orphan receptor (ROR)γt (T 17 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 17 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 17 cells). Most CD8 RORγt T cells coexpressed T-bet, a lineage transcription factor for T 1 and T 1 development, suggesting that CD8 RORγt T cells undergo plasticity toward a T 17/1-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.