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首页> 外文期刊>The Journal of Experomental Medicine >Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
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Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells

机译:通过C5a受体和C3a受体发出的信号减弱了鼠类天然调节性T细胞的功能

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Thymus-derived (natural) CD4+ FoxP3+ regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4+CD25? T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses.
机译:胸腺来源的(天然)CD4 + FoxP3 +调节性T细胞(nT reg细胞)是免疫稳态和自我耐受性所必需的,但必须严格控制以扩大保护性免疫力。以前的发现是否将通过T细胞表达的C5a受体(C5aR)和C3a受体(C3aR)传输的信号与常规CD4 + CD25的激活,分化和扩增联系起来? T细胞(T转化细胞)提高了nT reg细胞上C3aR / C5aR信号传导可以生理调节nT reg细胞功能的可能性,从而进一步影响T细胞免疫应答的诱导强度。在这项研究中,我们证明nT reg细胞表达C3aR和C5aR,并且通过这些受体发出的信号抑制nT reg细胞的功能。在nT reg细胞中C3aR / C5aR信号转导的遗传和药理学阻断作用增强了体外和体内抑制作用,消除了自身免疫性结肠炎,并延长了异体皮肤移植的存活时间。机制涉及C3a / C5a诱导的AKT磷酸化,结果是转录因子Foxo1的磷酸化,导致nT reg细胞Foxp3表达降低。 C3a / C3aR和C5a / C5aR通过控制Foxp3表达来调节nT reg细胞功能的文献表明,靶向该途径可被用于操纵病原性或保护性T细胞应答。

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