Ly9 (SLAMF3) receptor differentially regulates iNKT cell development and activation in mice

Cuenca, Marta; Puñet-Ortiz, Joan; Ruart, Maria; Terhorst, Cox; Engel, Pablo

doi:10.1002/eji.201746925

Cited by 11 publications

(11 citation statements)

References 22 publications

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“…In agreement to this, Ly9 −/− mice have increased thymic iNKT2 but very few iNKT1 cells [99]. However, this skewed subset distribution is not observed in the periphery [99], pointing to the possibility that the sub-lineage committed iNKT cells retain some degree of plasticity. Indeed, once they exit the thymus, iNKT cells can reprogram themselves depending on the signaling cues they receive in the periphery [57].…”

Section: Slam-sap Signals In Inkt Cell Lineage Differentiationmentioning

confidence: 75%

“…Furthermore, SFR-KO mice display reduced incidence of T-bet + PLZF lo iNKT1 cells but increased proportions of GATA-3 + PLZF hi iNKT2 and RORγt + PLZF int iNKT17 cells, highlighting a novel role of SFRs in iNKT cell lineage differentiation [93]. In agreement to this, Ly9 −/− mice have increased thymic iNKT2 but very few iNKT1 cells [99]. However, this skewed subset distribution is not observed in the periphery [99], pointing to the possibility that the sub-lineage committed iNKT cells retain some degree of plasticity.…”

Section: Slam-sap Signals In Inkt Cell Lineage Differentiationmentioning

confidence: 87%

“…Consistently, SLAM-SLAM interactions between iNKT and dendritic cells are required for iNKT cell production of Th2 cytokines like IL-4 and IL-10 but not IFN-γ [112]. In contrast, activation of the Ly9 receptor with an agonistic monoclonal antibody impairs iNKT cell cytokine production [99]. Based on these reports, it appears that signals generated by SFRs can positively or negatively regulate iNKT cell cytokine production.…”

Section: Slam-sap-fyn In Inkt Cell Functionmentioning

confidence: 99%

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SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function

Bahal

Hashem

Nichols

et al. 2019

IJMS

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Invariant natural killer T (iNKT) cells are a unique T cell lineage that develop in the thymus and emerge with a memory-like phenotype. Accordingly, following antigenic stimulation, they can rapidly produce copious amounts of Th1 and Th2 cytokines and mediate activation of several immune cells. Thus, it is not surprising that iNKT cells play diverse roles in a broad range of diseases. Given their pivotal roles in host immunity, it is crucial that we understand the mechanisms that govern iNKT cell development and effector functions. Over the last two decades, several studies have contributed to the current knowledge of iNKT cell biology and activity. Collectively, these studies reveal that the thymic development of iNKT cells, their lineage expansion, and functional properties are tightly regulated by a complex network of transcription factors and signaling molecules. While prior studies have clearly established the importance of the SLAM-SAP-Fyn signaling axis in iNKT cell ontogenesis, recent studies provide exciting mechanistic insights into the role of this signaling cascade in iNKT cell development, lineage fate decisions, and functions. Here we summarize the previous literature and discuss the more recent studies that guide our understanding of iNKT cell development and functional responses.

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Section: Slam-sap Signals In Inkt Cell Lineage Differentiationmentioning

confidence: 75%

Section: Slam-sap Signals In Inkt Cell Lineage Differentiationmentioning

confidence: 87%

Section: Slam-sap-fyn In Inkt Cell Functionmentioning

confidence: 99%

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SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function

Bahal

Hashem

Nichols

et al. 2019

IJMS

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“…iNKT cells are selected on high-affinity self-glycolipid ligands presented by the MHC class I-like molecule CD1d (18) which triggers their unique developmental program (19). Their selection uniquely requires co-stimulation via SLAM (signaling lymphocyte-activation molecule) family members and the tyrosine kinase Fyn (20–32) as discussed below. Once selected in stage 0, iNKT cells pass through complex activation, expansion, maturation and differentiation processes, termed stages 1–3 (Figure 1).…”

Section: Natural Killer T (Nkt) Cells and Cd1d-mediated Antigen Presementioning

confidence: 99%

The Role of Adaptor Proteins in the Biology of Natural Killer T (NKT) Cells

Gerth

Mattner

2019

Front. Immunol.

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Adaptor proteins contribute to the selection, differentiation and activation of natural killer T (NKT) cells, an innate(-like) lymphocyte population endowed with powerful immunomodulatory properties. Distinct from conventional T lymphocytes NKT cells preferentially home to the liver, undergo a thymic maturation and differentiation process and recognize glycolipid antigens presented by the MHC class I-like molecule CD1d on antigen presenting cells. NKT cells express a semi-invariant T cell receptor (TCR), which combines the Vα14-Jα18 chain with a Vβ2, Vβ7, or Vβ8 chain in mice and the Vα24 chain with the Vβ11 chain in humans. The avidity of interactions between their TCR, the presented glycolipid antigen and CD1d govern the selection and differentiation of NKT cells. Compared to TCR ligation on conventional T cells engagement of the NKT cell TCR delivers substantially stronger signals, which trigger the unique NKT cell developmental program. Furthermore, NKT cells express a panoply of primarily inhibitory NK cell receptors (NKRs) that control their self-reactivity and avoid autoimmune activation. Adaptor proteins influence NKT cell biology through the integration of TCR, NKR and/or SLAM (signaling lymphocyte-activation molecule) receptor signals or the variation of CD1d-restricted antigen presentation. TCR and NKR ligation engage the SH2 domain-containing leukocyte protein of 76kDa slp-76 whereas the SLAM associated protein SAP serves as adaptor for the SLAM receptor family. Indeed, the selection and differentiation of NKT cells selectively requires co-stimulation via SLAM receptors. Furthermore, SAP deficiency causes X-linked lymphoproliferative disease with multiple immune defects including a lack of circulating NKT cells. While a deletion of slp-76 leads to a complete loss of all peripheral T cell populations, mutations in the SH2 domain of slp-76 selectively affect NKT cell biology. Furthermore, adaptor proteins influence the expression and trafficking of CD1d in antigen presenting cells and subsequently selection and activation of NKT cells. Adaptor protein complex 3 (AP-3), for example, is required for the efficient presentation of glycolipid antigens which require internalization and processing. Thus, our review will focus on the complex contribution of adaptor proteins to the delivery of TCR, NKR and SLAM receptor signals in the unique biology of NKT cells and CD1d-restricted antigen presentation.

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“…Studies of our groups using Ly9 (CD229)‐deficient mice indicate that this receptor acts as a negative regulator of the development and homeostasis of innate‐like CD8 + and iNKT cells, and innate‐like B cells such as marginal zone B cells . Moreover, Ly9 (CD229)‐deficient mice spontaneously develop features of systemic autoimmunity, such as the production of antibodies against dsDNA, nucleosome and antinuclear antibodies .…”

Section: Introductionmentioning

confidence: 99%

Viral CD229 (Ly9) homologs as new manipulators of host immunity

Angulo

Cuenca

Martínez-Vicente

et al. 2019

Journal of Leukocyte Biology

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The signaling lymphocytic activation molecule family (SLAMF) of receptors plays crucial roles during innate and adaptive immune responses. The SLAMF member CD229 (Ly9, SLAMF3) is a homophilic receptor predominantly expressed on the surface of B and T cells. CD229 acts as a cosignaling molecule, regulating lymphocyte homoeostasis and activation. To promote viral replication and survival in their hosts, viruses have developed sophisticated mechanisms to combat and avoid immune surveillance. Many of these strategies rely on host defense genes captured during the process of virus–host coevolution. In particular, large DNA viruses devote a wide range of proteins to interfere with almost every host immune pathway. Given that CD229 is critically involved in regulating immune responses, it is not surprising that viruses have designed tactics to mimic or interfere with this receptor. The discovery, in recent years, that some viruses have hijacked CD229 genes from their hosts, incorporating them as an integral part of their genomes, or have evolved proteins to directly target CD229, indicates that this is the case. While it is still an emerging area of research, the present review discusses these viral molecules and their potential in immune modulation. A more detailed understanding of the mechanisms of action and the functional implications of these new viral CD229 mimics may not only provide seminal information on viral immune evasion mechanisms but also, unveil unrecognized aspects of CD229 immune functions.

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Ly9 (SLAMF3) receptor differentially regulates iNKT cell development and activation in mice

Cited by 11 publications

References 22 publications

SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function

SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function

The Role of Adaptor Proteins in the Biology of Natural Killer T (NKT) Cells

Viral CD229 (Ly9) homologs as new manipulators of host immunity

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