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

Hui Xu,Guang-Xian Zhang,Gregory B Carey,Jingxian Yang,Abdolmohamad Rostami,Yaping Yan,Mark S Williams,Hongmei Li,Derya Unutmaz

doi:10.1371/journal.pone.0013780

Hui Xu, Guang-Xian Zhang + Show 7 more

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https://doi.org/10.1371/journal.pone.0013780

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Abstract

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

Highlights

MS4a4B is a novel member of the MS4A gene family which is characterized by their structural features, with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions [1]
Western blotting with surface-biotin labeling of primary T cells and histological studies with confocal microscopy of MS4a4Bexpressing retrovirus-infected EL4 thymoma cells showed that MS4a4B was expressed on cell surface (Fig. 1A and B), suggesting that MS4a4B may potentially interact with other cell membrane proteins in T cell regulation
MS4a4B was constitutively expressed in primary naıve T cells, levels of its expression were markedly increased upon stimulation by mitogen concanavalin A (Con A)

Summary

Introduction

MS4a4B is a novel member of the MS4A gene family (membrane-spanning 4-domain family, subfamily A, MS4As) which is characterized by their structural features, with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions [1]. The MS4A family includes CD20, FceRIb, HTm4 and at least 26 novel members [2,3]. Chromosome mapping shows that the genes for human CD20, FceRIb, HTm4 and 12 recently identified MS4A members are located in chromosome 11q12-q13 [4,5], which is associated with increased susceptibility to allergy and atopic asthma. Our knowledge of the MS4A family is derived mainly from studies on CD20, HTm4 and FceRIb. CD20 is a nonglycosylated, plasmamembrane associated protein in B cells [7,8], which disappears when B cells differentiate into plasma cells [9,10]. An increasing body of data suggests that CD20 is involved in calcium signaling and more extensively associated with B cell activation, differentiation and apoptosis [12,13]. 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 cellmediated immune responses [1,19,20], suggesting its importance in adaptive immunity

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