Consequence of the SLAM-SAP Signaling Pathway in Innate-like and Conventional Lymphocytes

“…Finally, the parallel requirement for c-Myc in regulating V␣14i NKT and memory CD8 T cell development is of particular interest in view of recent speculation about the general role of signaling molecules in determining the fate of "innate-like" vs adaptive T cell lineages (42,43). In this context, Tec kinases such as Itk have been found to be necessary for the development of conventional T cells but dispensable for the generation of memory phenotype (CD44 high CD122 high ) CD8 T cells, which can be considered to be representative of innate T cells in the sense that they are IL-15 dependent and armed for rapid IFN-␥ production.…”

Section: Discussionmentioning

confidence: 99%

Selective Requirement for c-Myc at an Early Stage of Vα14i NKT Cell Development

Mycko

Ferrero

Wilson

et al. 2009

The Journal of Immunology

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Vα14 invariant (Vα14i) NKT cells are a subset of regulatory T cells that utilize a semi-invariant TCR to recognize glycolipids associated with monomorphic CD1d molecules. During development in the thymus, CD4+CD8+ Vα14i NKT precursors recognizing endogenous CD1d-associated glycolipids on other CD4+CD8+ thymocytes are selected to undergo a maturation program involving sequential expression of CD44 and NK-related markers such as NK1.1. The molecular requirements for Vα14i NKT cell maturation, particularly at early developmental stages, remain poorly understood. In this study, we show that CD4-Cre-mediated T cell-specific inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biological activities, selectively impairs Vα14i NKT cell development without perturbing the development of conventional T cells. In the absence of c-Myc, Vα14i NKT cell precursors are blocked at an immature CD44lowNK1.1− stage in a cell autonomous fashion. Residual c-Myc-deficient immature Vα14i NKT cells appear to proliferate normally, cannot be rescued by transgenic expression of BCL-2, and exhibit characteristic features of immature Vα14i NKT cells such as high levels of preformed IL-4 mRNA and the transcription factor promyelocytic leukemia zinc finger. Collectively our data identify c-Myc as a critical transcription factor that selectively acts early in Vα14i NKT cell development to promote progression beyond the CD44lowNK1.1− precursor stage.

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“…CD244 signal transduction involves interactions between SH2 domain-containing adaptor proteins and the tyrosine-based motif TIYXX(V/I) (referred to as an immunoreceptor tyrosine-based switch motif, ITSM) in the cytoplasmic domain of CD244. Three cytoplasmic SH2 domain-containing adaptor proteins recognize this motif: SAP (also known as SH2D1A or DSHP), EAT-2 (also known as SH2D1B) and ERT (also known as sh2d1c) 44,45. Humans have functional genes encoding SAP and EAT-2, but ERT is expressed only in mice; its ortholog is a pseudogene in humans.…”

Section: Nkg2d Receptor Complexesmentioning

confidence: 99%

Up on the tightrope: natural killer cell activation and inhibition

2008

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Natural killer (NK) cells circulate through the blood, lymphatics and tissues, on patrol for the presence of transformed or pathogen-infected cells. As almost all NK cell receptors bind to host-encoded ligands, signals are constantly being transmitted into NK cells, whether they interact with normal or abnormal cells. The sophisticated repertoire of activating and inhibitory receptors that has evolved to regulate NK cell activity ensures that NK cells protect hosts against pathogens, yet prevents deleterious NK cell-driven autoimmune responses. Here I highlight recent advances in our understanding of the structural properties and signaling pathways of the inhibitory and activating NK cell receptors, with a particular focus on the ITAM-dependent activating receptors, the NKG2D-DAP10 receptor complexes and the CD244 receptor system. NK cells, like other members of the innate immune system, were once considered nonspecific in their interactions with tumors or virus-infected cells. A seminal study noted that NK cells can kill certain tumor cells lacking MHC class I, yet spare the same tumors expressing MHC class I (ref. 1). This ability to attack cells 'missing self' predicted the existence of inhibitory receptors on NK cells, and it revealed the mechanism whereby NK cells engage in surveillance for transformed or virus-infected cells that have downregulated expression of MHC class I in an effort to avoid recognition by CD8 + cytotoxic T lymphocytes. However, missing from the missing-self hypothesis was any molecular basis for how NK cells are activated when they encounter tumors or virus-infected cells, or how in certain circumstances NK cells do efficiently recognize and kill tumors or virus-infected cells that maintain expression of MHC class I. Even after the discovery of the inhibitory NK cell receptors, activation of NK cells against MHC class I-deficient cells was generally considered nonspecific. Not so anymore. Many activating NK cell receptors and pathways have recently been identified, and the interplay between the inhibitory receptors and activating receptors are being defined. This review highlights the predominant signaling pathways that regulate the responses of NK cells encountering potential target cells. Inhibitory NK receptorsNK cells express a repertoire of inhibitory receptors that regulate their activation. Some inhibitory NK receptors are specific for MHC class I, whereas others bind non-MHC ligands (Supplementary Table 1 online). Some of these inhibitory NK receptors, such as killer cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptors (LILRs), are monomeric type I glycoproteins of the immunoglobulin superfamily, whereas others, suchCorrespondence should be addressed to L.L.L. (E-mail: lewis.lanier@ucsf.edu).. Note: Supplementary information is available on the Nature Immunology website. COMPETING INTERESTS STATEMENTThe author declares competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/natur...

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Consequence of the SLAM-SAP Signaling Pathway in Innate-like and Conventional Lymphocytes

Cited by 107 publications

References 98 publications

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

Selective Requirement for c-Myc at an Early Stage of Vα14i NKT Cell Development

Up on the tightrope: natural killer cell activation and inhibition

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