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

CD8 super(+) 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. We have previously observed that CD8 super(+) 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 super(+)CD161 super(+) T cells in healthy donors and those with hepatitis C virus and defined a population of CD8 super(+) 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 g-t, P = 6 oe- 10 super(-9); RUNX2, P = 0.004), cytokine receptors (e.g., IL-23R, P = 2 oe- 10 super(-7); IL-18 receptor, P = 4 oe- 10 super(-6)), and chemokine receptors (e.g., CCR6, P = 3 oe- 10 super(-8); CXCR6, P = 3 oe- 10 super(-7); CCR2, P = 4 oe- 10 super(-7)). CD161 super(+)CD8 super(+) T cells were markedly enriched in tissue samples and coexpressed IL-17 with high levels of IFN-g 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 super(+) T cells in normal humans and a substantial fraction of tissue-infiltrating CD8 super(+) T cells in chronic inflammation. Such cells play a role in the pathogenesis of chronic hepatitis and arthritis and potentially in other infectious and inflammatory diseases of man.