CD45 表达的数量差异揭示了 CD45 在 B 细胞发育、耐受性和存活中的功能。,Proceedings of the National Academy of Sciences of the United States of America

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CD45 表达的数量差异揭示了 CD45 在 B 细胞发育、耐受性和存活中的功能。
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2012 Jan 3 , DOI: 10.1073/pnas.1117374108
Julie Zikherman ₁ , Kristin Doan , Ramya Parameswaran , William Raschke , Arthur Weiss

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受体样酪氨酸磷酸酶 CD45 通过使 src 家族激酶的抑制性酪氨酸去磷酸化，正向调节抗原受体信号。由于表达了部分多余的酪氨酸磷酸酶 CD148，CD45 缺陷小鼠无法完全揭示 CD45 在 B 细胞中的作用。然而，CD45 和 CD148 双重缺陷的小鼠在 B 细胞发育中表现出非常早期的阻滞，从而掩盖了 CD45 的后期作用。为了克服这些限制，我们在这里利用等位基因系列小鼠，其中 CD45 表达被广泛滴定 (0-180%)。尽管 CD45 的高表达会抑制 T 细胞受体 (TCR) 信号传导，但我们表明 CD45 在 B 细胞受体 (BCR) 信号传导过程中起纯粹的正调节作用。与夸大的 BCR 信号一致，CD45 表达的增加驱动了骨髓中受体编辑的增强和脾脏中滤泡和边缘区 B 细胞的大量丢失。在 B 细胞耐受的 IgHEL/sHEL 模型的背景下，如此高的 CD45 表达将无能转化为缺失。出乎意料的是，在该模型系统中消除自身抗原 sHEL 以阻止克隆缺失未能挽救成熟 B 细胞的存活。相反，高 CD45 表达会降低 B 细胞激活因子受体 (BAFFR) 的表达并以细胞内在方式抑制 B 细胞激活因子 (BAFF) 诱导的 B 细胞存活。综上所述，我们的研究结果揭示了 CD45 功能如何在 T 细胞和 B 细胞中分化，以及自身反应性 B 细胞在发育过程中如何被审查。

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Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival.

The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor signaling by dephosphorylating the inhibitory tyrosine of the src family kinases. CD45-deficient mice fail to fully unmask the role of CD45 in B cells because of the expression of a partially redundant tyrosine phosphatase, CD148. However, mice that are doubly deficient in CD45 and CD148 exhibit a very early block in B-cell development, thereby obscuring later roles for CD45. To overcome these limitations, here we take advantage of an allelic series of mice in which CD45 expression is titrated broadly (0-180%). Although high expression of CD45 inhibits T-cell receptor (TCR) signaling, we show that CD45 plays a purely positive regulatory role during B-cell receptor (BCR) signaling. In concert with exaggerated BCR signaling, increasing CD45 expression drives enhanced receptor editing in the bone marrow and profound loss of follicular and marginal zone B cells in the spleen. In the context of the IgHEL/sHEL model of B-cell tolerance, such high CD45 expression transforms anergy into deletion. Unexpectedly, elimination of the autoantigen sHEL in this model system in order to block clonal deletion fails to rescue survival of mature B cells. Rather, high CD45 expression reduces B-cell activating factor receptor (BAFFR) expression and inhibits B-cell activating factor (BAFF)-induced B-cell survival in a cell-intrinsic manner. Taken together, our findings reveal how CD45 function diverges in T cells and B cells, as well as how autoreactive B cells are censored as they transit development.

更新日期：2017-01-31

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