A single amino acid determines the immunostimulatory activity of interleukin 10.
A single amino acid determines the immunostimulatory activity of interleukin 10.
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DOI：
10.1084/jem.191.2.213
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发表时间：
2000-01-17
影响因子：
15.3
通讯作者：
Bromberg, J S
中科院分区：
文献类型：
--
作者：
Ding, Y;Qin, L;Kotenko, S V;Pestka, S;Bromberg, J S
人类和小鼠来源的细胞白细胞介素 10 (cIL-10) 与 Epstein-Barr 病毒 BCRF-I 基因产物（称为病毒 IL-10 (vIL-10)）具有广泛的序列和结构同源性。尽管这些细胞因子具有许多共同的免疫抑制特性，但 vIL-10 缺乏 cIL-10 对某些细胞类型的多种免疫刺激活性。目前尚未定义这种二分法的分子和细胞基础。在这里，我们证明 cIL-10 第 87 位的单氨基酸异亮氨酸是其免疫刺激功能所必需的。用对应于 vIL-10 残基的丙氨酸取代 cIL-10 中的异亮氨酸，消除了胸腺细胞、肥大细胞和同种异体抗原反应的免疫刺激活性，同时保留了抑制干扰素 γ 产生和延长心脏同种异体移植物存活的免疫抑制活性。相反，在 vIL-10 中用异亮氨酸取代丙氨酸会将其转化为具有免疫刺激活性的 cIL-10 样分子。这种单一保守残基的改变显着影响配体对受体的亲和力；然而，亲和力的变化并不一定会以可预测的方式改变生物反应的特定活性。这些结果表明 IL-10 受体-配体相互作用和随后的生物反应的复杂调节。这些结果表明，vIL-10 可能代表捕获并选择性突变的 cIL-10 基因，该基因通过导致无效的宿主免疫反应而有利于病毒发病机制。在刺激或抑制方向上操纵 IL-10 活性的能力对于调节疾病治疗的免疫反应可能具有实用价值，并且对于确定 IL-10 活性的哪些方面对正常 T 细胞反应重要具有理论价值。
Cellular interleukin 10s (cIL-10s) of human and murine origin have extensive sequence and structural homology to the Epstein-Barr virus BCRF-I gene product, known as viral IL-10 (vIL-10). Although these cytokines share many immunosuppressive properties, vIL-10 lacks several of the immunostimulatory activities of cIL-10 on certain cell types. The molecular and cellular bases for this dichotomy are not currently defined. Here, we show that the single amino acid isoleucine at position 87 of cIL-10 is required for its immunostimulatory function. Substitution of isoleucine in cIL-10 with alanine, which corresponds to the vIL-10 residue, abrogates immunostimulatory activity for thymocytes, mast cells, and alloantigenic responses while preserving immunosuppressive activity for inhibition of interferon γ production and prolongation of cardiac allograft survival. Conversely, substitution of alanine with isoleucine in vIL-10 converts it to a cIL-10–like molecule with immunostimulatory activity. This single conservative residue alteration significantly affects ligand affinity for receptor; however, affinity changes do not necessarily alter specific activities for biologic responses in a predictable fashion. These results suggest complex regulation of IL-10 receptor–ligand interactions and subsequent biological responses. These results demonstrate that vIL-10 may represent a captured and selectively mutated cIL-10 gene that benefits viral pathogenesis by leading to ineffective host immune responses. The ability to manipulate the activity of IL-10 in either a stimulatory or suppressive direction may be of practical value for regulating immune responses for disease therapy, and of theoretical value for determining what aspects of IL-10 activity are important for normal T cell responses.