Induction of Lectin-like Transcript 1 (LLT1) Protein Cell Surface Expression by Pathogens and Interferon-γ Contributes to Modulate Immune Responses

Germain, Claire; Meier, Anders; Jensen, Teis; Knapnougel, Perrine; Poupon, Gwénola; Lazzari, Anne; Neisig, Anne; Håkansson, Katarina; Dong, Tao; Wagtmann, Nicolai; Galsgaard, Elizabeth D.; Spee, Pieter; Braud, Véronique M.

doi:10.1074/jbc.m111.285312

Cited by 114 publications

(195 citation statements)

References 41 publications

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“…Antibody staining shows that human LLT1 can be induced on activated cells, as GC B cells from children suffering from chronic and recurrent tonsillitis triggered by viral and bacterial infections, TLR-activated DCs, activated NK and T cells after IFN-γ treatment, and TCRactivated T cells. It is not expressed on the surface of circulating lymphocytes [22,23]. In rodents, antibody staining has revealed a broad constitutive surface expression of Clr-b on hematopoietic tissue, and a tissue-specific expression of Clr-f on intestinal epithelial cells [40].…”

Section: Discussionmentioning

confidence: 99%

“…LLT1 is not expressed by resting cells but is upregulated on the surface of various leukocytes upon activation [22,23]. It is also induced in epithelial cells in the lung following RSV infection or activation with proinflammatory cytokines or TLR3 ligands [24].…”

Section: Introductionmentioning

confidence: 99%

“…NKR-P1A has a clear inhibitory effect on human NK-cell functions. In contrast, in T cells NKR-P1A stimulates proliferation and IFN-γ production upon stimulation by LLT1-expressing B cells and costimulates IL-17 secretion following CD3 cross-linking [20,23]. The human NKC also encodes two NKR-P1 related molecules termed KLRF1 (NKp80) and KLRF2 (NKp65), which binds the CLEC2B (AICL) and CLEC2A (KACL) ligands encoded within the same region [25].…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of a conserved pair of NKR‐P1 receptors expressed by NK cells and T lymphocytes in liver and gut

et al. 2014

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Natural killer cell receptor protein 1 (NKR-P1) molecules are C-type lectin-like receptors modulating cellular responses toward target cells expressing C-type lectin-like related (Clr) molecules. Although the function of the prototypic rat NKR-P1A receptor and its inhibitory counterpart NKR-P1B are known, little is known about NKR-P1F and NKR-P1G apart from their promiscuity for Clr ligands. Here we generated mAbs against both receptors for phenotypic and functional analyses in rat tissues. NKR-P1F induced redirected lysis and robust Ca 2+ signaling in NK cells, which were prevented by simultaneous engagement of NKR-P1G. NKR-P1G also inhibited NK-cell lysis of Clr transfectants. NKR-P1F was expressed by most NK cells and NKR-P1A + T cells in all tissues analyzed, and by many NKR-P1A − intestinal T cells, while NKR-P1G was expressed by subsets of these cells with highest prevalence in gut and liver. In the intraepithelial compartment, the proportion of NKR-P1A + and NKR-P1F + cells was high at birth and thereafter declined, while NKR-P1B + and NKR-P1G + cells increased with age. Expression levels were also modulated by cytokines, with an increase of NKR-P1B and NKR-P1G induced by inflammatory cytokines, and a reduction of NKR-P1A by TGF-β. The physiological impact of NKR-P1 receptors might thus be dependent on age, tissue, and inflammatory status.Keywords: C-type lectin-related molecules r NK-cell receptors r NKR-P1 r Rodent Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNatural killer (NK) cells are innate lymphoid cells with the ability to eliminate virally infected cells and transformed or allogeneic cells. They produce cytokines early in the immune response, and play an important role in shaping the immune response, e.g. in the context of inflammation and transplantation. These tasks are controlled by a wide range of receptors with different functions and ligands, such as Ly49 receptors, which recognize both classical and nonclassical MHC class I molecules, as well as MHC Correspondence: Dr. Lise Kveberg e-mail: lise.kveberg@rr-research.no class I-like virally encoded ligands [1][2][3]. Another family of MHCbinding receptors is the conserved NKG2/CD94 heterodimers, which bind the nonclassical MHC molecule HLA-E in human [4], its rodent homologue Qa-1 b in the mouse [5,6] and RT.BM1 in the rat [7]. Both the Ly49 and NKG2/CD94 receptor families contain inhibitory and activating members. NKG2D is a promiscuous activating receptor, recognizing several MHC class I-related ligands frequently upregulated upon cellular stress and associated with viral infection and malignant transformation [8].The activating NK cytotoxicity receptors react with several virus-derived and endogenous ligands [9,10].One of the earliest NK-cell receptors to be characterized was the NK-cell receptor protein 1A (NKR-P1A) in the rat, which is C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 502Lise Kveberg et al. Eur. J. Immunol. 2015. 45: 501-...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional characterization of a conserved pair of NKR‐P1 receptors expressed by NK cells and T lymphocytes in liver and gut

et al. 2014

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“…Notably, while NKRP1A is expressed in NK and NKT cells, NKRP1A is an important marker for Th17 cells, and its expression is induced in a retinoic acid-related orphan receptor C-dependent manner. Therefore, the NKRP1A-LLT1 recognition regulates the immune functions of NK, NKT, and Th17 cells [20].In addition to NKRP1A, NKp65 and NKp80 also belong to the human NKRP1 subfamily. The ligands of these molecules are keratinocyte-associated C-type lectin (KACL) and activationinduced C-type lectin (AICL), respectively, and they all belong to the CLEC2 subfamily [21,22].…”

mentioning

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confidence: 99%

Crystal structure of extracellular domain of human lectin‐like transcript 1 (LLT1), the ligand for natural killer receptor‐P1A

et al. 2015

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Emerging evidence has revealed the pivotal roles of C-type lectin-like receptors (CTLRs) in the regulation of a wide range of immune responses. Human natural killer cell receptor-P1A (NKRP1A) is one of the CTLRs and recognizes another CTLR, lectin-like transcript 1 (LLT1) on target cells to control NK, NKT and Th17 cells. The structural basis for the NKRP1A-LLT1 interaction was limitedly understood. Here, we report the crystal structure of the ectodomain of LLT1. The plausible receptor-binding face of the C-type lectin-like domain is flat, and forms an extended β-sheet. The residues of this face are relatively conserved with another CTLR, keratinocyte-associated C-type lectin, which binds to the CTLR member, NKp65. A LLT1-NKRP1A complex model, prepared using the crystal structures of LLT1 and the keratinocyte-associated C-type lectin-NKp65 complex, reasonably satisfies the charge consistency and the conformational complementarity to explain a previous mutagenesis study. Furthermore, crystal packing and analytical ultracentrifugation revealed dimer formation, which supports a complex model. Our results provide structural insights for understanding the binding modes and signal transduction mechanisms, which are likely to be conserved in the CTLR family, and for further rational drug design towards regulating the LLT1 function.Keywords: Cell surface receptor r Crystal structure r C-type lectin-like receptor r Natural killer cell r Protein-protein interactions Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Katsumi Maenaka e-mail: maenaka@pharm.hokudai.ac.jp * Equal contribution.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1606 S. Kita et al. Eur. J. Immunol. 2015. 45: 1605-1613 Introduction Natural killer (NK) cells are a component of innate immunity, and display cytotoxic activities against tumor cells and virally infected cells [1,2]. The activities of NK cells are precisely regulated by activating and inhibitory signals, through diverse receptors on the cell surface [3][4][5]. These receptors are encoded in two genomic regions, the leukocyte receptor complex (chromosome 19 in human) [6] and the NK gene complex (chromosome 12 in human) [7,8]. The leukocyte receptor complex encodes the NK receptors of the immunoglobulin (Ig) superfamily, such as killer Ig-like receptors and leukocyte Ig-like receptors, whereas the NK gene complex region encodes the NK receptors of the C-type lectinlike receptors (CTLRs). The CTLRs are subdivided into two groups, according to their expression patterns. Killer cell lectin-like receptors (KLRs) are expressed in NK cells, and C-type lectin receptors (CLECs) are expressed in non-NK cells [9]. The ligands of KLRs are (1) major histocompatibility complex (MHC) class I molecules and relatives, and (2) CLECs. The former members include CD94, the NKG2 subfamily [10], and the Ly49 subfamily [11], and the latter members are the NK receptor-P1 (NKRP1) subfamily [12,13]. The NKRP1 su...

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Immune checkpoint CD161/LLT1‐associated immunological landscape and diagnostic value in oral squamous cell carcinoma

Hu,

Dong,

Xie

et al. 2024

The Journal of Pathology CR

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An active host adaptive response is characterized by the existence of programmed cell death protein 1 (PD‐1)+/IFN‐γ+ cytotoxic T cells and IFN‐γ‐induced PD‐L1+ tumor cells (TCs), which predicts high response rate to anti‐PD‐1/L1 therapy. Recently, CD161 and its ligand LLT1 (CLEC2D) have been identified as an emerging checkpoint for immunotherapy. Clarifying its heterogeneous clinical expression pattern and its immune landscape is a prerequisite for maximizing the response rate of CD161 blockade therapy in a specific population of oral squamous cell carcinoma (OSCC) patients. Here, we investigated the expression pattern of CD161/LLT1 and its association with major immunocytes (T cells, B cells, NK cells, and macrophages) by multiplex immunofluorescence, immunohistochemistry, and flow cytometry in 109 OSCC tissues and 102 peripheral blood samples. TCs showed higher LLT1 levels than tumor infiltrating lymphocytes (TILs), whereas CD161 was highly expressed in CD8+ T cells at the tumor front, which was decreased in paracancerous tissue. High expression of TC‐derived LLT1 (LLT1TC) conferred poor clinical outcomes, whereas higher CD161+ and LLT1+ TILs were associated with better prognosis. Meanwhile, patients with high LLT1TC showed a decreased ratio of CD8+/Foxp3+ T cells in situ, but CD161+ TILs correlated with more peripheral CD3+ T cells. Interestingly, treatment of OSCC patients with nivolumab (anti‐PD‐1) could restore tumoral CD161/LLT1 signal. Furthermore, an OSCC subgroup characterized by high LLT1+ TCs and low CD161+CD8+ T cells showed fewer peripheral T cells and a higher risk of lymph node metastasis, leading to a shorter 5‐year survival time (29%). More LLT1TC at the invasive front was another risk characteristic of exhausted T cells. In conclusion, in view of this heterogeneity, the LLT1/CD161 distribution pattern should be determined before CD161‐based immunotherapy.

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Induction of Lectin-like Transcript 1 (LLT1) Protein Cell Surface Expression by Pathogens and Interferon-γ Contributes to Modulate Immune Responses

Cited by 114 publications

References 41 publications

Functional characterization of a conserved pair of NKR‐P1 receptors expressed by NK cells and T lymphocytes in liver and gut

Functional characterization of a conserved pair of NKR‐P1 receptors expressed by NK cells and T lymphocytes in liver and gut

Crystal structure of extracellular domain of human lectin‐like transcript 1 (LLT1), the ligand for natural killer receptor‐P1A

Immune checkpoint CD161/LLT1‐associated immunological landscape and diagnostic value in oral squamous cell carcinoma

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