Stimulatory Function of gp49A, a Murine Ig-Like Receptor, in Rat Basophilic Leukemia Cells

Ono, M.; Inui, Makoto; Yuasa, Takae; Takai, Toshiyuki

doi:10.4049/jimmunol.165.9.4970

Cited by 22 publications

(10 citation statements)

References 65 publications

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“…a CD36 is a scavenger receptor involved in inflammation 21 . b Gp49a lacks an inhibitory ITIM and has a stimulatory activity in inflammation 22 . c Gp49b/Lilrb4/ILT3 is a member of the immunoglobulin superfamily that is expressed, among others, by macrophages, mast cells and T-cells.…”

Section: Resultsmentioning

confidence: 99%

Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia

et al. 2012

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Although cure rates for acute lymphoblastic leukemia (ALL) have increased, development of resistance to drugs and patient relapse are common. The environment in which the leukemia cells are present during the drug treatment is known to provide significant survival benefit. Here, we have modeled this process by culturing murine Bcr/Abl-positive acute lymphoblastic leukemia cells in the presence of stroma while treating them with a moderate dose of two unrelated drugs, the farnesyltransferase inhibitor lonafarnib and the tyrosine kinase inhibitor nilotinib. This results in an initial large reduction in cell viability of the culture and inhibition of cell proliferation. However, after a number of days, cell death ceases and the culture becomes drug-tolerant, enabling cell division to resume. Using gene expression profiling, we found that the development of drug resistance was accompanied by massive transcriptional upregulation of genes that are associated with general inflammatory responses such as the metalloproteinase MMP9. MMP9 protein levels and enzymatic activity were also increased in ALL cells that had become nilotinib-tolerant. Activation of p38, Akt and Erk correlated with the development of environment-mediated drug resistance (EMDR), and inhibitors of Akt and Erk in combination with nilotinib reduced the ability of the cells to develop resistance. However, inhibition of p38 promoted increased resistance to nilotinib. We conclude that development of EMDR by ALL cells involves changes in numerous intracellular pathways. Development of tolerance to drugs such as nilotinib may therefore be circumvented by simultaneous treatment with other drugs having divergent targets.

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Section: Resultsmentioning

confidence: 99%

Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia

et al. 2012

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“…The two major subtypes, gp49A and gp49B, are encoded by two different genes adjacent to each other [12,26,27]. gp49A has a short cytoplasmic tail and does not harbor any specific motif for signal transduction nor bind to the FcR common g subunit, while gp49A is considered to be expressed as a homodimer and elicits activation signals in vitro [28]. In contrast, gp49B contains two ITIM in its cytoplasmic portion, and inhibits activation signals upon cellular engagement with other activating receptors by recruiting SHP-1 to phosphotyrosylated ITIM [27,29].…”

Section: Introductionmentioning

confidence: 99%

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

et al. 2008

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Dendritic cells (DC) play pivotal roles in the induction and regulation of both innate and acquired immunity. DC express several cell-surface immune inhibitory receptors. However, little is known about their potential immunoregulatory functions in the context of T-cell activation. Here we report that murine gp49B, a member of the immunoglobulin superfamily, harboring immunoreceptor tyrosine-based inhibitory motifs, is expressed on DC and downregulates cellular activity to prevent the excessive activation of T cells in vitro and in vivo. Bone marrow-derived DC (BMDC) from newly generated gp49B-deficient (gp49B À/À ) mice induced enhanced proliferation and IL-2 release of antigen-specific CD4 1 and CD8 1 T cells compared with BMDC from wild-type mice, in a cell-cell contact manner. The enhanced proliferation by gp49B À/À BMDC was also observed in allogeneic CD4 1 and CD8 1 T cells. Moreover, the transfer of allogeneic BALB/c splenocytes into C57BL/6 gp49B À/À mice induced severe acute graft-versus-host disease with an augmented upregulation of CD86 on CD11c 1 splenic gp49B À/À DC, while transfer of C57BL/6 gp49B À/À splenocytes into BALB/c mice did not, suggesting the exacerbation of the disease was due, at least in part, to augmented activation of recipient gp49B À/À DC. These findings demonstrate a novel regulatory role of gp49B in the function of DC.Key words: Antigen presentation Á Costimulation Á DC Á Regulatory receptor Á Tolerance IntroductionDendritic cells (DC) are professional antigen-presenting cells that recognize a diverse repertoire of antigens and present them to naïve T cells for the induction of acquired immunity [1]. DC are also related to innate immunity by producing cytokines such as both type I and II IFN, or by activating NK cells [2,3]. In addition, recent reports revealed that a subset of DC maintains peripheral tolerance in the steady state [4], showing that DC play a pivotal role in the induction of immune responses including autoimmunity.On the DC surface, a variety of structurally different immunoreceptors that regulate DC and T-cell functions have been found, including CD80, CD86, CD40, and various Ig superfamily and lectin family molecules [5]. Among them, a group of paired Ig superfamily receptors, termed Ig-like receptors, have been attracting the interest of many researchers because they are expressed on various subsets of DC and are considered to contribute to the development or activation of DC [6][7][8][9][10]. Generally, Ig-like receptors are subdivided into two types, namely activating and inhibitory receptors, and in some cases they are expressed on hematopoietic cells in a pair-wise manner [11][12][13][14]. Most activating receptors associate with homodimeric subunits containing ITAM, such as the FcR common g chain and KARAP/DAP12 [15,16], and deliver positive signals into the cells through interaction with their ligands [17]. For instance, the uptake of immune complexes through activating FcR for IgG 2426augments DC maturation, leading to efficient antigen presentation [18...

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“…Although highly homologous to gp49B1 (88% overall amino acid identity), gp49A has a much shorter cytoplasmic domain, lacks the two ITIMs present in gp49B1, and activates mast cells when crosslinked by Ab (18,19,21). gp49B1 inhibits mast cell activation in vitro by recruiting Src homology protein-1 when co-cross-linked with Fc⑀RI (22).…”

mentioning

confidence: 99%

The gp49B1 Inhibitory Receptor Regulates the IFN-γ Responses of T Cells and NK Cells

Gu¹,

Laouar²,

Wan³

et al. 2003

The Journal of Immunology

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The magnitude and diversity of Ag-specific T cell effector activity have been proposed to be controlled by an integration of positive signals transduced by the TCR and negative signals originating from inhibitory cell surface molecules. Although the lectin family of NK cell-associated inhibitory receptors has been reported to regulate the function of murine CTLs, gp49B1, the Ig superfamily member is not known to be expressed on T cells. Moreover, the consequences of the lack of an endogenously expressed NK cell-associated inhibitory receptor on T cell functions are not known. We report that gp49B1 is expressed by nearly all activated CD8 and CD4 T cells in addition to NK cells during an immune response to viral, bacterial, or tumor challenge. Kinetics of gp49B1 expression parallel functional capability and subside in the memory phase. Following vaccinia viral infection, IFN-γ production by both subsets of T cells and NK cells is enhanced in gp49B1-deficient mice compared with gp49B1+/+ mice. The stimulation threshold for IFN-γ production is also lower in gp49B1-deficient T cells. In contrast, no significant differences were observed in the cytotoxic responses. We conclude that gp49B1 is a unique inhibitory receptor that is induced in multiple lineages of innate and adaptive immune cells during an infection and controls their IFN-γ, but not cytotoxic responses.

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Stimulatory Function of gp49A, a Murine Ig-Like Receptor, in Rat Basophilic Leukemia Cells

Cited by 22 publications

References 65 publications

Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia

Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

The gp49B1 Inhibitory Receptor Regulates the IFN-γ Responses of T Cells and NK Cells

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