Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells

Abstract

Mucosal-associated invariant T (MAIT) cells IntroductionMainstream T cells display a very diverse repertoire of antigen receptors, which enable these cells to respond to a wide variety of antigens presented by polymorphic major histocompatibility complex (MHC) molecules. During development, interactions between the T cells and selecting MHC class II and I molecules on thymic epithelial cells lead to the specific features of CD4 and CD8 T-cell lineage. However, 2 "innate-like" T lymphocytes, the natural killer T (NKT) and mucosal-associated invariant T (MAIT) cells, follow different ontogenic pathways with selection by nonpolymorphic MHC class Ib molecules. 1 Human MAIT cells express the semi-invariant T-cell receptor (TCR; iV␣7.2-J␣33) and are selected by the MHC class Ib molecule, MR1 on hematopoietic cells, which confer peculiar features. 2,3 Indeed, MAIT cells are enriched in the intestinal lamina propria and are numerous in the peripheral blood of healthy subjects. They are present in cord blood in small numbers with a naive phenotype, whereas in adults they represent approximately 10% of mature CD8 or CD4 Ϫ CD8 Ϫ (DN) T cells and display an effector-memory phenotype. We recently showed that MAIT cells specifically react against antigen-presenting cells (APCs), fed with a wide variety of bacteria and yeasts but not viruses, and display protective activity in experimental bacterial infection models. 4,5 In humans, they are defined as CD161 hi IL-18R␣ ϩ V␣7.2 ϩ ␥␦ Ϫ CD3 ϩ lymphocytes. 3,4 Either CD161 or IL-18R␣ expression at the cell surface, together with the V␣7.2 segment, allows for the unequivocal identification of MAIT cells in both peripheral blood and tissues. 3,4 CD161 (KLRB1, NKRP1A) is a C-type lectin family member, part of the NK complex. 6 Ligands for CD161 have been described only recently, and blocking or cross-linking CD161 may modulate T-cell functions. 7-9 CD161 is also expressed by the majority of NK cells and diverse subsets of T lymphocytes that include TCR-␥␦ T cells and most NKT cells. CD161 expression is found on a significant proportion of tissue-infiltrating T cells, such as the intestine and liver. [10][11][12] The frequency of these cells varies in certain pathologic conditions, such as cancer and viral or autoimmune diseases. [12][13][14][15] Recently, it has been demonstrated that a subset of naive cord blood CD4 T cells express CD161 and are precursors of peripheral, mature, Th17 T cells. 16 CD161 expression seems to correlate with interleukin-17 (IL-17) secretion by CD4 T cells. 17 Among TCR-␣␤ T cells, most of the CD161 ϩ T cells belong to the CD4 subset. However, CD8 T cells expressing CD161 can also be found, but their nature has just begun to be explored. CD161 ϩ CD8 T cells can be split into 2 different populations expressing intermediate or high levels of CD161. Two recent reports independently raised new findings on this latter subset. The first shows that CD161 hi CD8 T cells represent self-renewing memory cells, which survive chemotherapy. 18 These cells are absent from...

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…”

“…These subsets are clearly present at birth, suggesting that they are distinct populations with pre‐programmed functional differences. MAIT cells are only a small fraction of the CD161++ CD8+ T‐cell population in cord blood,83 but slowly expand with age, making up more than 90% of the CD161++ CD8+ T‐cell population in adults 11, 14. Both MAIT and non‐MAIT CD161++ CD8+ T‐cells share functional features, most notably the ability to respond to innate cytokines in the absence of TCR stimulation, due to their high expression of cytokine receptors such as IL‐18R and IL‐12R 9, 84.…”

“…In particular, they may make up to 30%–50% of all intrahepatic T‐cells, mediated by their expression of chemokine receptors such as CXCR6 and CCR6, which bind the chemokines CXCL16 and CCL20, respectively, that are constitutively expressed in the liver 11. Intrahepatic MAIT cells have been shown to be highly activated and express CD69, HLA‐DR and CD38, and are positioned around bile ducts within hepatic portal tracts 111, 118.…”

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

“…MAIT cells display an intrinsic effector‐memory phenotype – i.e. without the need for prior clonal expansion14 – typically CD45RA − CD45RO + CD95 Hi CD62L Lo CD44 Hi 2, 15, 16, 17 – and can rapidly secrete a range of pro‐inflammatory cytokines including tissue necrosis factor‐ α (TNF‐ α ), interleukin‐17 (IL‐17) and interferon‐ γ (IFN‐ γ ), and also the type 2 cytokine IL‐4 on TCR ligation 15, 17. 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.…”

“…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.…”