Genomic structure, alternative splicing, and physical mapping of the killer cell lectin-like receptor G1 gene (KLRG1), the mouse homologue of MAFA

Voehringer, David; Kaufmann, Martina; Pircher, Hanspeter

doi:10.1007/s002510000282

Cited by 23 publications

(26 citation statements)

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“…This family of receptors upon binding ligands uses an intracellular receptor chain tyrosine-based inhibitory motif (ITIM) to produce negative signals by recruiting cytoplasmic phosphotases. The most recent work has focused in the mouse on the Killer Cell Lectin Like Receptor G1 (KLRG1), which is the mouse homologue of the mast cell function-associated antigen (MAFA) and is expressed on natural killer (NK) cells and activated CD8 T cells (Voehringer et al, 2001). This is a type II transmembrane glycoprotein with an extracellular domain homologous to C-type lectins associated with N terminal cytoplasmic tails containing an ITIM motif that can recruit the hematopoietic cell phosphotase SHP-1 to the complex and result in an inhibitory signal being delivered to the cell (Long, 1999;Raulet et al, 2001).…”

Section: Senescence and Killer Cell Lectin Like Receptorsmentioning

confidence: 99%

Age‐related changes in the function of T cells

Aspinall

2003

Microscopy Res & Technique

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At the start of the last century in the United Kingdom, only 24% of the 587,830 deaths registered were of individuals over 65, but by the end of the century these figures had changed markedly. Of the 558,052 deaths in 1997, 84% were in the population over 65. This "right shift" in the survival curve is projected to continue. The UK Government Actuary's Department forecast that by 2020, 11.75 million people (19% of the population) will be over 65 rising to 15.1 million people (25% of the population) by 2040. Older members of society show infections of the urinary tract, respiratory tract, skin, soft tissue or intra-abdominal region, infectious endocarditis, bacterial meningitis, tuberculosis, and herpes zoster, at a higher incidence than among younger adults. Moreover, mortality rates for these diseases are often 2-3 times higher among elderly patients than younger individuals with the same disease. The higher morbidity and mortality from these infections, plus the increased prevalence of specific cancers and certain autoimmune diseases point to an immune system deteriorating with age. At the core of the immune system are the T cells and this review analyses possible causes for the changes in T cell function that may account for the deterioration of the immune system. Any intervention to reverse the decline in the immune system must have a rational basis built on a hypothesis-driven inquiry, and one such intervention process is presented here.

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Section: Senescence and Killer Cell Lectin Like Receptorsmentioning

confidence: 99%

Age‐related changes in the function of T cells

Aspinall

2003

Microscopy Res & Technique

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“…It is found in humans (1, 2), rats (3), and mice (4,5) and contains an ITIM in its cytoplasmic tail. The human KLRG1 gene maps to the NK gene complex (1), whereas the mouse homologue is located ϳ2 cM distant from this locus (6). In humans, 50 -80% of CD56 dim NK cells express KLRG1 (7), whereas in mice, kept under specific pathogen free conditions, KLRG1 is found on ϳ30% of NK cells (5).…”

Section: T He Killer Cell Lectin-like Receptor G1 (Klrg1)mentioning

confidence: 99%

Tumor-Associated E-Cadherin Mutations Affect Binding to the Killer Cell Lectin-Like Receptor G1 in Humans

Schwartzkopff

Gründemann

Schweier

et al. 2007

The Journal of Immunology

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The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and memory T cells in man and mice. Cadherins were recently identified as ligands for mouse KLRG1 but ligands for human KLRG1 have not yet been defined. In this study, we first demonstrate that human E-cadherin is a ligand for human KLRG1. This finding is remarkable because human and mouse KLRG1 show only an intermediate degree of homology (57% aa identity). In addition, we show that E-cadherin, expressed on K562 target cells, inhibited polyclonal human NK cells. Inhibition of NK cell function was observed consistently in three independent functional assays but the extent of inhibition was modest and required high expression of E-cadherin on target cells. E-cadherin function is often inactivated during development of human carcinomas and splice-site mutations resulting in in-frame loss of exon 8 or 9 occur frequently in diffuse type gastric carcinomas. Our experiments further revealed that interaction of human KLRG1 to E-cadherin was susceptible to these tumor-associated mutations and that KLRG1+ NK cells were triggered more easily by K562 target cells carrying these mutations in comparison to target cells expressing wild-type E-cadherin. These results also indicate that the E-cadherin binding sites important for homophilic interaction are also involved in KLRG1 binding. Taken together, these data demonstrate that the main adhesion molecule of epithelial tissue, E-cadherin, is involved in regulation of NK cells in both humans and mice.

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“…The molecule was first identified in the rat basophilic leukemia cell line RBL-2H3 and was originally termed mast cell function-associated Ag (MAFA). [10][11][12][13][14][15] In mice and humans, this well-conserved receptor is found on subsets of T and natural killer (NK) cells. [16][17][18][19][20][21][22][23][24] Cells that express KLRG1 include the most mature and recently activated NK cells as well as effector/memory T cells.…”

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Immunoregulatory functions of KLRG1 cadherin interactions are dependent on forward and reverse signaling

Banh

Fugère²,

Brossay

2009

Blood

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KLRG1 is an inhibitory receptor expressed on a subset of mature T and NK cells. Recently, E-, N-, and R-cadherin have been identified as ligands for KLRG1. Cadherins are a large family of transmembrane or membrane-associated glycoproteins that were thought to only bind specifically to other cadherins to mediate specific cell-to-cell adhesion in a Ca 2؉ -dependent manner. The consequences of cadherin KLRG1 molecular interactions are not well characterized. Here, we report that the first 2 extracellular domains of cadherin are sufficient to initiate a KLRG1-dependent signaling. We also demonstrate that KLRG1 engagement inhibits cadherin-dependent cellular adhesion and influences dendritic cell secretion of inflammatory cytokines, thereby exerting immunosuppressive effects. Consistent with this, engagement of cadherin by KLRG1 molecule induces cadherin tyrosine phosphorylation. Therefore, KLRG1/cadherin interaction leads to the generation of a bidirectional signal in which both KLRG1 and cadherin activate downstream signaling cascades simultaneously. Taken IntroductionEpithelial cadherins (E-cadherins), neural cadherins (N-cadherins), and retinal cadherins (R-cadherins) are part of the classical cadherins. These ubiquitously expressed cell adhesion molecules are a large family of transmembrane or membrane-associated glycoproteins comprising an extracellular domain containing 5 cadherin repeats (EC1-5) responsible for cell-to-cell interactions, a transmembrane domain, and a cytoplasmic domain that is linked to the actin cytoskeleton. Typically, cadherins mediate calciumdependent homophilic adhesion, thereby promoting association of cells expressing the same cadherin family members to form adherens junctions. 1,2 The formation of adherens junctions is dependent on the association of cadherin's cytoplasmic tail with ␤-catenin and its partners. 1 Numerous biologic processes, including homeostasis and embryogenesis, rely on the selective adherence of one adhesion molecule to another through precise intermolecular interactions. 3 The spatiotemporal regulation of cadherin expression and function are vital to tissue morphogenesis, providing a basis for the formation of epithelial layers of the skin and intestine. [4][5][6] Aside from their homophilic adhesion mode, E-, N-, and R-cadherins have been recently reported to bind in a heterophilic manner with killer cell lectin-like receptor G1 (KLRG1). [7][8][9] KLRG1 is a transmembrane inhibitory receptor belonging to the C-type lectin-like superfamily that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. The molecule was first identified in the rat basophilic leukemia cell line RBL-2H3 and was originally termed mast cell function-associated Ag (MAFA). [10][11][12][13][14][15] In mice and humans, this well-conserved receptor is found on subsets of T and natural killer (NK) cells. [16][17][18][19][20][21][22][23][24] Cells that express KLRG1 include the most mature and recently activated NK cells as well as effector/memory T cells. [...

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Genomic structure, alternative splicing, and physical mapping of the killer cell lectin-like receptor G1 gene (KLRG1), the mouse homologue of MAFA

Cited by 23 publications

References 0 publications

Age‐related changes in the function of T cells

Age‐related changes in the function of T cells

Tumor-Associated E-Cadherin Mutations Affect Binding to the Killer Cell Lectin-Like Receptor G1 in Humans

Immunoregulatory functions of KLRG1 cadherin interactions are dependent on forward and reverse signaling

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