Cutting Edge: Ly9 (CD229), a SLAM Family Receptor, Negatively Regulates the Development of Thymic Innate Memory-like CD8+ T and Invariant NKT Cells

Sintes, Jordi; Cuenca, Marta; Romero, Xavier; Bastos, Ricardo; Terhorst, Cox; Angulo, Ana; Engel, Pablo

doi:10.4049/jimmunol.1202435

Cited by 37 publications

(52 citation statements)

References 17 publications

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“…As previously reported (20, 22), we found that the homotypic SAP-dependent receptors Slamf1, Slamf3, Slamf5, and Slamf6 are moderately to highly expressed by DP TCRβ low thymocytes. Although Slamf2 is highly expressed by these cells, its receptor, Slamf4, is virtually absent, suggesting that this heterophilic interaction does not play a role during homotypic DP-DP contacts (Figure S1D in Supplementary Material).…”

Section: Resultssupporting

confidence: 89%

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SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors

Calisto

Wang

et al. 2014

Front. Immunol.

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Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8+ T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1 + 6]−/− and Slamf[1 + 5 + 6]−/−B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8+ T cells slightly increased in the Slamf[1 + 5 + 6]−/−, but not in the Slamf[1 + 6]−/− strain, suggesting that Slamf5 may function as a negative regulator of innate CD8+ T cell development. Accordingly, Slamf5−/− B6 mice showed an exclusive expansion of innate CD8+ T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7−/− strain showed an expansion of both splenic innate CD8+ T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3−/− BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZFhi) NKT cells and innate CD8+ T cells significantly increased in the SAP-independent Slamf8−/− BALB/c strain. In summary, these results show that NKT and innate CD8+ T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8+ T cells.

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Section: Resultssupporting

confidence: 89%

“…Cognate activation of NKT cells is restricted to CD1d–lipid complexes and is modulated by SAP and at least three members of the SLAMF of receptors (20–22). The homophilic interactions of Slamf1 and Slamf6 between DP thymocytes are particularly important for the development of the NKT cell lineage (20).…”

Section: Introductionmentioning

confidence: 99%

SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors

Calisto

Wang

et al. 2014

Front. Immunol.

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“…The link between SLAMF3 expression and proliferation was demonstrated in vitro and then validated by the inhibition of HCC progression in Nude mice xenografted with SLAMF3-overexpressing HCC cells. It was recently reported that SLAMF3 has a similar role in lymphocytes; in contrast to SLAMF1 and SLAMF6, SLAMF3 has a negative effect on the signalling pathways required for innate-like lymphocyte development in the thymus [37]. The observed effect may be attributed to both decrease in the proliferation of cells over-expressing SLAMF3 and the induction of apoptosis.…”

Section: Discussionmentioning

confidence: 97%

Identification of SLAMF3 (CD229) as an Inhibitor of Hepatocellular Carcinoma Cell Proliferation and Tumour Progression

et al. 2013

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Although hepatocellular carcinoma (HCC) is one of the most common malignancies and constitutes the third leading cause of cancer-related deaths, the underlying molecular mechanisms are not fully understood. In the present study, we demonstrate for the first time that hepatocytes express signalling lymphocytic activation molecule family member 3 (SLAMF3/CD229) but not other SLAMF members. We provide evidence to show that SLAMF3 is involved in the control of hepatocyte proliferation and in hepatocellular carcinogenesis. SLAMF3 expression is significantly lower in primary human HCC samples and HCC cell lines than in human healthy primary hepatocytes. In HCC cell lines, the restoration of high levels of SLAMF3 expression inhibited cell proliferation and migration and enhanced apoptosis. Furthermore, SLAMF3 expression was associated with inhibition of HCC xenograft progression in the nude mouse model. The restoration of SLAMF3 expression levels also decreased the phosphorylation of MAPK ERK1/2, JNK and mTOR. In samples from resected HCC patients, SLAMF3 expression levels were significantly lower in tumorous tissues than in peritumoral tissues. Our results identify SLAMF3 as a specific marker of normal hepatocytes and provide evidence for its potential role in the control of proliferation of HCC cells.

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“…For example, the Slamf8-deficient mice have normal iNKT cell numbers but with an enlarged PLZF hi iNKT2 compartment [64]. Because the Slamf8 molecules signal independently of SAP and Slamf8-encoding mRNA is expressed in dendritic cells and fibroblasts in the thymus but not DP thymocytes, it is likely that Slamf8 functions differently than the other Slam-family molecules in affecting iNKT cell development [30,64,65,66]. Instead, these results suggest that DC cells or fibroblasts might provide external signals, which are affected by the absence of Slamf8, to developing iNKT cells.…”

Section: Cell Extrinsic Signalsmentioning

confidence: 99%

Development of invariant natural killer T cells

Gapin

2016

Current Opinion in Immunology

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Invariant natural killer T (iNKT) cells develop into functionally distinct subsets. Each subset expresses a unique combination of transcription factors that regulate cytokine gene transcription upon activation. The tissue distribution and localization within tissues also varies between subsets. Importantly, the relative abundance of the various subsets is directly responsible for altering several immunological parameters, which subsequently affect the immune response. Here, I review recent advances in our understanding of the molecular regulation of iNKT cell subset development.

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Cutting Edge: Ly9 (CD229), a SLAM Family Receptor, Negatively Regulates the Development of Thymic Innate Memory-like CD8+ T and Invariant NKT Cells

Cited by 37 publications

References 17 publications

SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors

SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors

Identification of SLAMF3 (CD229) as an Inhibitor of Hepatocellular Carcinoma Cell Proliferation and Tumour Progression

Development of invariant natural killer T cells

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