Analysis of CD161 expression on human CD8⁺ T cells defines a distinct functional subset with tissue-homing properties

CD8⁺ T lymphocytes play a key role in host defense, in particular against important persistent viruses, although the critical functional properties of such cells in tissue are not fully defined.Wehave previously observed that CD8⁺ T cells specific for tissue-localized viruses such as hepatitis C virus express high levels of the C-type lectin CD161. To explore the significance of this, we examined CD8 ⁺CD161⁺ T cells in healthy donors and those with hepatitis C virus and defined a population of CD8⁺ T cells with distinct homing and functional properties. These cells express high levels of CD161 and a pattern of molecules consistent with type 17 differentiation, including cytokines (e.g., IL-17, IL-22), transcription factors (e.g., retinoic acid-related orphan receptor γ-t, P = 6 × 10^-9; RUNX2, P = 0.004), cytokine receptors (e.g., IL-23R, P = 2 × 10^-7; IL-18 receptor, P = 4 × 10^-6), and chemokine receptors (e.g., CCR6, P = 3 × 10^-8; CXCR6, P = 3 × 10^-7; CCR2, P = 4 × 10^-7). CD161⁺CD8⁺ T cells were markedly enriched in tissue samples and coexpressed IL-17 with high levels of IFN-γ and/or IL-22. The levels of polyfunctional cells in tissue was most marked in those with mild disease (P = 0.0006). These data define a T cell lineage that is present already in cord blood and represents as many as one in six circulating CD8⁺ T cells in normal humans and a substantial fraction of tissue-infiltrating CD8⁺ T cells in chronic in.ammation. Such cells play a role in the pathogenesis of chronic hepatitis and arthritis and potentially in other infectious and inflammatory diseases of man.