MS4A4B Is a GITR-Associated Membrane Adapter, Expressed by Regulatory T Cells, Which Modulates T Cell Activation

Howie, Duncan; Nolan, Kathleen F.; Daley, Stephen R.; Butterfield, Emma; Adams, Elizabeth; Garcia-Rueda, Hugo; Thompson, Claire; Saunders, N.; Cobbold, Stephen; Tone, Yukiko; Tone, Masahide; Waldmann, Herman

doi:10.4049/jimmunol.0901070

Cited by 59 publications

(53 citation statements)

References 38 publications

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“…The functions of other members remain largely unclear. Since we cloned MS4a4B from the thymus of C57BL/6 mice, data from our studies and others have shown that MS4a4B is highly expressed in T cells and is closely related to the regulation of CD4 + T cell-mediated immune responses [1], [19], [20], suggesting its importance in adaptive immunity.…”

Section: Introductionmentioning

confidence: 75%

MS4a4B, a CD20 Homologue in T Cells, Inhibits T Cell Propagation by Modulation of Cell Cycle

Yan

Williams

et al. 2010

PLoS ONE

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MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural killer cells (NK) and some T cell lines. But its expression in all malignant T cells, including thymoma and T hybridoma tested, was silenced. Interestingly, its expression was regulated during T cell activation. Viral vector-driven overexpression of MS4a4B in primary T cells and EL4 thymoma cells reduced cell proliferation. In contrast, knockdown of MS4a4B accelerated T cell proliferation. Cell cycle analysis showed that MS4a4B regulated T cell proliferation by inhibiting entry of the cells into S-G2/M phase. MS4a4B-mediated inhibition of cell cycle was correlated with upregulation of Cdk inhibitory proteins and decreased levels of Cdk2 activity, subsequently leading to inhibition of cell cycle progression. Our data indicate that MS4a4B negatively regulates T cell proliferation. MS4a4B, therefore, may serve as a modulator in the negative-feedback regulatory loop of activated T cells

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Section: Introductionmentioning

confidence: 75%

MS4a4B, a CD20 Homologue in T Cells, Inhibits T Cell Propagation by Modulation of Cell Cycle

Yan

Williams

et al. 2010

PLoS ONE

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“…It has been shown recently that other MS4A family members are capable of transmitting cellular signals by binding to regulatory proteins; for example, MS4A4B is able to cluster with the GC-inducible costimulatory molecule GITR in supramolecular complexes in the plasma membrane in cis lowering the threshold for GITR activation in regulatory T-cells. 38 Similarly, MS4A8A could cluster with as yet unidentified surface receptors in cis to alter their activation threshold or signaling behavior, especially in GC-treated macrophages.…”

Section: Discussionmentioning

confidence: 99%

Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2‐like tumor‐associated macrophages expressing the novel CD20 homolog MS4A8A

Schmieder

Schledzewski

Michel

et al. 2010

Intl Journal of Cancer

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Tumor-associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE-1 1 M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow-derived macrophages (BMDMs) by combining M2 mediators (IL-4, glucocorticoids) and tumor-conditioned media (TCM). Admixture of MS4A8A 1 TCM/IL-4/GCtreated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage-like cells displayed a special gene signature. Admixture of these MS4A8A 1 Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF-jB activation and of the MAPK JNK and ERK did not show relevant effects, the p38a/b MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A 1 TAM may serve as a novel cellular target for selective cancer therapy.

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“…Furthermore, Th1 and Th17 cells also increased microglial production of inflammatory cytokines [52]. To date, lots of researchers have confirmed that the MS4A family gene overexpression can increase activation of T cells [39,54]. MS4A4B as a member of the MS4A family gene had been found to regulate apoptosis and survival of activated T cells [39][40][41].…”

Section: Potential Roles For Ms4a Cluster In Admentioning

confidence: 99%

MS4A Cluster in Alzheimer’s Disease

Tan

2014

Mol Neurobiol

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Several variants within membrane-spanning 4-domains subfamily A (MS4A) gene cluster have recently been implicated the association of Alzheimer's disease (AD) by serial recent genome-wide association studies (GWAS). As cell membrane proteins, MS4A family members are found to participate in the regulation of calcium signaling which have been widely discussed in neurodegeneration and AD. Besides, although the MS4A family members are poorly characterized, an important role in immunity has already been identified for several members of this cluster (such as MS4A1, MS4A2, and MS4A4B), indicating the possible involvement of MS4A gene cluster in AD pathogenesis. In this article, we briefly summarize the structure, localization, and function of MS4A gene cluster, review recent genetic and expression findings concerning the association of MS4A gene cluster with AD pathogenesis, and also speculate the possible roles of MS4A gene cluster in this disease. Based on the contributing effects of MS4A gene cluster in AD pathogenesis, targeting MS4A gene cluster might provide new opportunities for AD treatment.

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MS4A4B Is a GITR-Associated Membrane Adapter, Expressed by Regulatory T Cells, Which Modulates T Cell Activation

Cited by 59 publications

References 38 publications

MS4a4B, a CD20 Homologue in T Cells, Inhibits T Cell Propagation by Modulation of Cell Cycle

MS4a4B, a CD20 Homologue in T Cells, Inhibits T Cell Propagation by Modulation of Cell Cycle

Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2‐like tumor‐associated macrophages expressing the novel CD20 homolog MS4A8A

MS4A Cluster in Alzheimer’s Disease

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