CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential

Abstract

NK1.1 and its human homolog CD161 are expressed on NK cells, subsets of CD4⁺ and CD8⁺ T cells, and NKT cells. While the expression of NK1.1 is thought to be inhibitory to NK cell function, it is reported to play both costimulatory and coinhibitory roles in T-cells. CD161 has been extensively studied and characterized on subsets of T-cells that are MR1-restricted, IL-17 producing CD4⁺ (T_H17 MAIT cells) and CD8⁺ T cells (Tc17 cells). Non-MAIT, MR1-independent CD161-expressing T-cells also exist and are characterized as generally effector memory cells with a stem cell like phenotype. Gene expression analysis of this enigmatic subset indicates a significant enhancement in the expression of cytotoxic granzyme molecules and innate like stress receptors in CD8⁺NK1.1⁺/CD8⁺CD161⁺ cells in comparison to CD8⁺ cells that do not express NK1.1 or CD161. First identified and studied in the context of viral infection, the role of CD8⁺CD161⁺ T-cells, especially in the context of tumor immunology, is still poorly understood. In this review, the functional characteristics of the CD161-expressing CD8⁺ T cell subset with respect to gene expression profile, cytotoxicity, and tissue homing properties are discussed, and application of this subset to immune responses against infectious disease and cancer is considered.

Keywords: CD161; KLRB1; T-cell; TH1 polarization; effector memory.

Figure 1

CD161-expressing CD8⁺ T cells are classified as tissue homing MAIT (Mucosal Associated Invariant T) cells, cytotoxic Tc17 cells, or T_mem (stem cell like memory) cells that display tissue homing and enhanced cytotoxic characteristics in addition to memory. T_mem cells respond to viral infections and can be activated by antigen presenting cells loaded with viral peptides or intracellular bacteria. In response to infection or antigenic stimulation, T_mem cells upregulate chemokine and stress receptors and secrete granzyme, INF-γ, and in some instances, IL-17. CD161⁺ T_mem cells home to vital organs like lungs, liver, gut, pancreas, and brain where they respond to viral infections and also display anti-tumor properties.