A novel isoform of the Ly108 gene ameliorates murine lupus

Keszei, Márton; Detre, Cynthia; Rietdijk, Svend; Muñoz, Pilar; Romero, Xavier; Berger, Scott B.; Calpe, Silvia; Liao, Guojun; Castro, Wilson; Julien, Aimée; Wu, Yinglong; Shin, Dong‐Mi; Sancho, Jaime; Zubiaur, Mercedes; Morse, Herbert C.; Morel, Laurence; Engel, Pablo; Wang, Ninghai; Terhorst, Cox

doi:10.1084/jem.20101653

Cited by 55 publications

(98 citation statements)

References 39 publications

(79 reference statements)

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“…This interpretation is consistent with the finding of functional isoforms of several SLAMF genes with antagonistic activities (8,12,13,44). SLAMF6, LY9, and CD244 are differentially expressed on the surface of a wide variety of hematopoietic cells, including CMV-permissive macrophages and dendritic cells, and effector NK and cytotoxic CD8 ϩ T cells known to play a central role in the control of CMV infection.…”

Section: Discussionsupporting

confidence: 89%

“…Engagement of the N-terminal Ig domains of SLAMF receptors with their cognate ligands results in the recruitment of these intracellular molecules, leading to signaling transduction events that ultimately modulate several immune responses (7,11). Moreover, coexpression of distinct isoforms of the SLAMF receptors, e.g., alternative cytoplasmic tails of SLAMF1 (12) or functionally distinct isoforms of CD244 and SLAMF6 (8,13,14), further refines these responses.…”

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confidence: 99%

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Signaling Lymphocytic Activation Molecule Family Receptor Homologs in New World Monkey Cytomegaloviruses

Pérez-Carmona

Farré

Martínez-Vicente

et al. 2015

J Virol

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Throughout evolution, large DNA viruses have been usurping genes from their hosts to equip themselves with proteins that restrain host immune defenses. Signaling lymphocytic activation molecule (SLAM) family (SLAMF) receptors are involved in the regulation of both innate and adaptive immunity, which occurs upon engagement with their ligands via homotypic or heterotypic interactions. Here we report a total of seven SLAMF genes encoded by the genomes of two cytomegalovirus (CMV) species, squirrel monkey CMV (SMCMV) and owl monkey CMV (OMCMV), that infect New World monkeys. Our results indicate that host genes were captured by retrotranscription at different stages of the CMV-host coevolution. The most recent acquisition led to S1 in SMCMV. S1 is a SLAMF6 homolog with an amino acid sequence identity of 97% to SLAMF6 in its ligand-binding N-terminal Ig domain. We demonstrate that S1 is a cell surface glycoprotein capable of binding to host SLAMF6. Furthermore, the OMCMV genome encodes A33, an LY9 (SLAMF3) homolog, and A43, a CD48 (SLAMF2) homolog, two soluble glycoproteins which recognize their respective cellular counterreceptors and thus are likely to be viral SLAMF decoy receptors. In addition, distinct copies of further divergent CD48 homologs were found to be encoded by both CMV genomes. Remarkably, all these molecules display a number of unique features, including cytoplasmic tails lacking characteristic SLAMF signaling motifs. Taken together, our findings indicate a novel immune evasion mechanism in which incorporation of host SLAMF receptors that retain their ligand-binding properties enables viruses to interfere with SLAMF functions and to supply themselves with convenient structural molds for expanding their immunomodulatory repertoires. IMPORTANCEThe way in which viruses shape their genomes under the continual selective pressure exerted by the host immune system is central for their survival. Here, we report that New World monkey cytomegaloviruses have broadly captured and duplicated immune cell receptors of the signaling lymphocyte activation molecule (SLAM) family during host-virus coevolution. Notably, we demonstrate that several of these viral SLAMs exhibit exceptional preservation of their N-terminal immunoglobulin domains, which results in maintenance of their ligand-binding capacities. At the same time, these molecules present distinctive structural properties which include soluble forms and the absence of typical SLAM signaling motifs in their cytoplasmic domains, likely reflecting the evolutionary adaptation undergone to efficiently interfere with host SLAM family activities. The observation that the genomes of other large DNA viruses might bear SLAM family homologs further underscores the importance of these molecules as a novel class of immune regulators and as convenient scaffolds for viral evolution.A s the immune system has evolved mechanisms to overcome viral infections, viruses have been forced to develop specific tactics to counteract host immune surveillance. Large DNA viruses su...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Signaling Lymphocytic Activation Molecule Family Receptor Homologs in New World Monkey Cytomegaloviruses

Pérez-Carmona

Farré

Martínez-Vicente

et al. 2015

J Virol

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“…Subsequent experiments largely focused upon the role of Ly108 in this phenotype, for which differences in the expression of several splice variants of this gene have been noted. In autoimmune mouse strains, expression of Ly108-1 is increased, whereas Ly108-2 expression is decreased and Ly108-H1 is absent (24,25). We confirmed similarly altered expression of these splice variants in c1 congenic T cells (N. Talaei and J. Wither, unpublished observations).…”

Section: Discussionsupporting

confidence: 79%

“…We confirmed similarly altered expression of these splice variants in c1 congenic T cells (N. Talaei and J. Wither, unpublished observations). Notably, absence of a Ly108-H1 splice variant was shown to promote differentiation of IFN-g-producing T cells (25). Therefore, it is likely that this contributes to the enhanced production of IFN-g by c1 congenic T cells in T cell-DC cocultures (Fig.…”

Section: Discussionmentioning

confidence: 92%

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

Talaei

Tao

Manion

et al. 2015

The Journal of Immunology

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We showed previously that C57BL/6 congenic mice with an introgressed homozygous 70 cM (125.6 Mb) to 100 cM (179.8 Mb) interval on c1 from the lupus-prone New Zealand Black (NZB) mouse develop high titers of antinuclear Abs and severe glomerulonephritis. Using subcongenic mice, we found that a genetic locus in the 88–96 cM region was associated with altered dendritic cell (DC) function and synergized with T cell functional defects to promote expansion of pathogenic proinflammatory T cell subsets. In this article, we show that the promoter region of the NZB gene encoding the SLAM signaling pathway adapter molecule EWS-activated transcript 2 (EAT-2) is polymorphic, which results in an ∼70% reduction in EAT-2 in DC. Silencing of the EAT-2 gene in DC that lacked this polymorphism led to increased production of IL-12 and enhanced differentiation of T cells to a Th1 phenotype in T cell–DC cocultures, reproducing the phenotype observed for DC from congenic mice with the NZB c1 70–100 cM interval. SLAM signaling was shown to inhibit production of IL-12 by CD40L-activated DCs. Consistent with a role for EAT-2 in this inhibition, knockdown of EAT-2 resulted in increased production of IL-12 by CD40-stimulated DC. Assessment of downstream signaling following CD40 cross-linking in the presence or absence of SLAM cross-linking revealed that SLAM coengagement blocked activation of p38 MAPK and JNK signaling pathways in DC, which was reversed in DC with the NZB EAT-2 allele. We conclude that EAT-2 negatively regulates cytokine production in DC downstream of SLAM engagement and that a genetic polymorphism that disturbs this process promotes the development of lupus.

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“…Since functional defects in both T and B lymphocytes are required for ANA production, it is possible that dysregulation of Ly108 isoform downstream signaling (derived from T:B engagement) might lead to disruption of peripheral tolerance and triggering of the autoimmune process in SLE. A third protein isoform, Ly108-H1, which is absent in two lupus-prone congenic animals has been recently identified (Keszei et al, 2011b). Ly108-H1 is encoded by a splice variant of Ly108 that lacks both exons 7 and 8.…”

Section: Slamf Spliced Variants and Their Role In Autoimmunitymentioning

confidence: 99%

SLAM Family Receptors and Autoimmunity

Sintes¹,

Bastos²,

Engel³

2011

Autoimmune Disorders - Pathogenetic Aspects

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A novel isoform of the Ly108 gene ameliorates murine lupus

Abstract: The expression of the new Ly108 isoform H1 weakens lupus-like disease of C57BL/6.Sle1b mice.

Cited by 55 publications

References 39 publications

Signaling Lymphocytic Activation Molecule Family Receptor Homologs in New World Monkey Cytomegaloviruses

Signaling Lymphocytic Activation Molecule Family Receptor Homologs in New World Monkey Cytomegaloviruses

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

SLAM Family Receptors and Autoimmunity

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