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

Abstract

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. We have 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 inflammation. Such cells play a role in the pathogenesis of chronic hepatitis and arthritis and potentially in other infectious and inflammatory diseases of man.

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…MAIT cells have been shown to detect a variety of microbes through the recognition of vitamin B metabolites presented by MR1 12, 81, 82. Furthermore, these cells were found to largely overlap with a unique subset of CD8+ T‐cells expressing CD161 at a high level, CD161++ CD8+ T‐cells 11, 15…”

“…Human peripheral blood CD8+ T‐cells can be divided into three distinct populations according to their relative expression level of the C‐type lectin‐like receptor CD161 15. These subsets are clearly present at birth, suggesting that they are distinct populations with pre‐programmed functional differences.…”

“…These cells share a functional phenotype with a family of other CD8+ T‐cells that express high levels of the C‐type lectin‐like receptor CD161 14. CD161 expression divides the CD8+ T‐cell population into three distinct functional subsets 15, 16. These subsets show varying degrees of innate (or NK‐like) activity according to their CD161 expression – thus CD161 expression can act as a marker of ‘innateness’ in T‐cell populations.…”

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

“…MAIT cells share some similarities with invariant natural killer T (iNKT) cells, which are implicated in many autoimmune conditions,18, 19 including expression of a semi‐invariant TCR, restriction by non‐classical MHC molecules, and expression of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF)20 although many differences exist, notably the nature of the ligands and the restriction molecule. Other significant features are the remarkable abundance of MAIT cells, which comprise approximately 5% of T cells in peripheral blood11, 17 and 20–40% of liver T cells in humans,15, 21 and their wide tissue distribution in blood, mucosal tissues, liver and joints 15, 19, 22, 23, 24, 25. A peculiarity of MAIT cell biology is that although MR1 expression is ubiquitous,3, 26 it is normally found only at very low levels on the cell surface 26, 27, 28.…”

Lights on MAIT cells, a new immune player in liver diseases

“…The authors suggest that these molecules allow LI-MAIT cells to be retained close to the bile ducts thereby inducing protection against potential bacterial infections from the gut. In vitro experiments reveal that biliary epithelium cells [6] can act as ''non-professional" antigen presenting cell by expressing MR1 and when exposed to E. coli by inducing MAIT cell degranulation and IFN-c secretion, this activation being MR1-dependent. Thus MAIT cells appear as efficient immune cells protecting the biliary mucosa.…”