CD161 is a marker of all human IL‐17‐producing T‐cell subsets and is induced by RORC

Maggi, Laura; Santarlasci, Veronica; Capone, Manuela; Peired, Anna Julie; Frosali, Francesca; Crome, Sarah Q.; Querci, Valentina; Fambrini, Massimiliano; Liotta, Francesco; Levings, Megan K.; Maggi, Enrico; Cosmi, Lorenzo; Romagnani, Sergio; Annunziato, Francesco

doi:10.1002/eji.200940257

Cited by 310 publications

(311 citation statements)

References 27 publications

Supporting

Mentioning

287

Contrasting

Unclassified

Order By: Relevance

“…Th17 cells have important roles in autoimmune and chronic inflammatory disorders, such as rheumatoid arthritis (31)(32)(33). The control of the Th17 responses has already yielded successful results in a clinical trial with rheumatoid arthritis patients (29).…”

Section: Resultsmentioning

confidence: 99%

Molecular Basis for LLT1 Protein Recognition by Human CD161 Protein (NKRP1A/KLRB1)

Kamishikiryo

Fukuhara

Okabe

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

Molecular Basis for LLT1 Protein Recognition by Human CD161 Protein (NKRP1A/KLRB1)

Kamishikiryo

Fukuhara

Okabe

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…The ability to secrete this cytokine has been previously correlated to the expression of RORC as well as CCR6 and CD161. 17 All these features are shared by the CD161 hi CD8 T-cell subset first implicated in viral hepatitis 10 before recently being further characterized by Billerbeck et al 11 These CD161 hi CD8 T cells share many characteristics with MAIT cells. They express an intermediate level of CD8␣␤ and many other markers that we found using phenotypic and transcriptional analysis, such as IL-23R and CCR2.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Dusséaux

Martin

Serriari

et al. 2011

Blood

843

1,303

View full text Add to dashboard Cite

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...

show abstract

Section: Introductionmentioning

confidence: 99%

“…We have also shown that virtually all human memory Th17 cells are contained within the CD161 + fraction of both circulating and tissue-infiltrating CD4 + T cells, and originate from CD161 + precursors present in umbilical cord blood and newborn thymus [9]. In humans, Th1 cells that derive from the shifting of Th17 cells have been defined as nonclassic Th1 cells [8,10], since they can be distinguished from classic Th1 cells by the expression of CD161, as expressed by Th17 cells [9][10][11].More recently, we have demonstrated that Th17 cells, unlike classic Th1 cells, do not proliferate in response to anti-CD3 plus anti-CD28 mAb stimulation; this unresponsiveness is due mainly to the inability of human Th17 cells to produce IL-2, which could be related to their reduced c-Fos, c-Jun, and NFAT activity [12]. Moreover, we found that the reduced activity of these transcription factors is associated with high expression of IL-4-induced gene 1 (IL4I1) mRNA, which encodes an L-phenylalanine oxidase able to downregulate the expression of CD3 chains in T cells, thus resulting in a poor ability to expand in response to TCR stimulation [12].…”

mentioning

confidence: 99%

IL‐4‐induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells

et al. 2013

Self Cite

View full text Add to dashboard Cite

Human Th17 cells have a limited proliferative capacity compared to other T-cell subsets.We have shown that human Th17 cells display impaired IL-2 production due to IL-4-induced gene 1 (IL4I1) upregulation. Here, we show that in human Th17 cells, IL4I1 also maintains high levels of Tob1, a member of the Tob/BTG (B-cell traslocation gene) antiproliferative protein family, which prevents cell-cycle progression mediated by TCR stimulation. Indeed, Th17 cells exhibited higher levels of Tob1 than Th1 cells in both resting and TCR-activated conditions. Accordingly, the expression of positive regulators of the cell cycle (cyclin A, B, C, and E and Cdk2), as well as of Skp2, which promotes Tob1 degradation, was lower in Th17 cells than in Th1 cells. Tob1 expression in human Th17 cells correlated with both RAR (retinoic acid receptor)-related orphan receptor C (RORC) and IL4I1 levels. However, RORC was not directly involved in the regulation of Tob1 expression, whereas IL4I1 silencing in Th17 cells induced a substantial decrease of Tob1 expression. These data suggest that IL4I1 upregulation in human Th17 cells limits their TCR-mediated expansion not only by blocking the molecular pathway involved in the activation of the IL-2 promoter, but also by maintaining high levels of Tob1, which impairs entry into the cell cycle. Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Francesco Annunziato e-mail: francesco.annunziato@unifi.it * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 654-661 HIGHLIGHTS 655 IntroductionActivated CD4 + T cells can be subdivided into lineages on the basis of their cytokine production, their specific transcription factor expression and their immunological function: T helper type 1 (Th1) cells express the transcription factor T-box expressed in T cells, secrete IFN-γ, and protect the host against intracellular infections; Th2 cells express the transcription factor GATA-3, secrete IL-4, IL-5, and IL-13, and mediate host defense against helminths; Th17 cells selectively produce IL-17A, express the transcription factor retinoic acid receptor (RAR) related orphan receptor γt, and are critical for the host's defense against extracellular pathogens [1][2][3][4]. Moreover, a subset of human IL-17A-producing CD4 + T cells was found to also produce IFN-γ (Th17/Th1) and both Th17 and Th17/Th1 cells exhibit plasticity toward the Th1 profile when cultured in the presence of . Similar findings were also reported in some murine models [5][6][7] suggesting that both human and murine Th17 cells probably represent a transient phenotype [8]. We have also shown that virtually all human memory Th17 cells are contained within the CD161 + fraction of both circulating and tissue-infiltrating CD4 + T cells, and originate from CD161 + precursors present in umbilical cord blood and newborn thymus [9]. In humans, Th1 cells that derive from the shif...

show abstract

CD161 is a marker of all human IL‐17‐producing T‐cell subsets and is induced by RORC

Cited by 310 publications

References 27 publications

Molecular Basis for LLT1 Protein Recognition by Human CD161 Protein (NKRP1A/KLRB1)

Molecular Basis for LLT1 Protein Recognition by Human CD161 Protein (NKRP1A/KLRB1)

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

IL‐4‐induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells

Contact Info

Product

Resources

About