Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock.
Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock.
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DOI：
10.1371/journal.pbio.1001149
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发表时间：
2011-09
期刊：
影响因子：
9.8
通讯作者：
Kaempfer R
中科院分区：
文献类型：
--
作者：
Arad G;Levy R;Nasie I;Hillman D;Rotfogel Z;Barash U;Supper E;Shpilka T;Minis A;Kaempfer R
细菌超抗原毒素直接结合到主要共刺激受体CD28的二聚体界面，诱导致命的细胞因子风暴，而阻止这种结合的肽可以抑制超抗原的致命性。细菌超级抗原，一个多样化的毒素家族，诱导炎症细胞因子风暴，可导致致命的休克。CD28是一种表达在T细胞上的同二聚体，通过与B7共配体的相互作用，在免疫反应中作为主要的共刺激配体发挥作用。然而，我们在这里表明，为了引发炎症细胞因子基因表达和毒性，超级抗原必须直接结合到CD28的二聚体界面上。阻止超抗原接近CD28就足以阻断其致死率。通过CD28二聚体界面的短肽模拟物和选择与超抗原在CD28中的结合位点竞争的肽来保护小鼠免受致命的超抗原攻击。超级抗原使用迄今未知功能的保守β-链/铰链/α-螺旋结构域与CD28接合。这种超抗原结构域的突变消除了炎症细胞因子基因的诱导和致死性。结构分析表明，当超抗原与T细胞上的T细胞受体和抗原呈递细胞上的主要组织相容性II类分子结合时，CD28可以很容易地作为第四元配合物中的第三个超抗原受体，CD28二聚体界面面向超抗原的β-链/铰链/α-螺旋结构域。我们的研究结果确定CD28同型二聚体界面是超级抗原的关键受体靶点。CD28作为一类微生物病原体，即超抗原毒素的受体的新作用，拓宽了病原体识别机制的范围。保护性免疫的诱导涉及炎性细胞因子的表达，即介导和响应免疫信号的蛋白质。然而，过度的细胞因子诱导可导致疾病，包括，在非常高的水平，致命的中毒性休克。葡萄球菌和链球菌的超级抗原是一个广泛的细菌蛋白毒素家族，可诱导这种致命的细胞因子风暴，其强度比正常免疫反应期间引发的强度高几个数量级。每一种免疫反应的关键参与者是共刺激受体CD28，它形成一种蛋白质二聚体来介导免疫反应。迄今为止，还不知道CD28能结合微生物成分。在这里，我们发现超级抗原可以选择CD28作为它们的受体，并且为了诱导细胞因子风暴，超级抗原必须直接结合到CD28的二聚体界面上。CD28和细菌超抗原之间的相互作用可以用肽（模仿完整的超抗原或CD28中的接触结构域的短蛋白片段）阻断。这些多肽减弱炎症细胞因子基因诱导，从而保护动物免受致命的中毒性休克。我们发现CD28是超抗原毒素的受体，这拓宽了微生物病原体识别机制的范围，并为设计抗中毒性休克的治疗方法提供了一种新的方法。
Bacterial superantigen toxins bind directly to the dimer interface of CD28, the principal co-stimulatory receptor, to induce a lethal cytokine storm, and peptides that prevent this binding can suppress superantigen lethality. Bacterial superantigens, a diverse family of toxins, induce an inflammatory cytokine storm that can lead to lethal shock. CD28 is a homodimer expressed on T cells that functions as the principal costimulatory ligand in the immune response through an interaction with its B7 coligands, yet we show here that to elicit inflammatory cytokine gene expression and toxicity, superantigens must bind directly into the dimer interface of CD28. Preventing access of the superantigen to CD28 suffices to block its lethality. Mice were protected from lethal superantigen challenge by short peptide mimetics of the CD28 dimer interface and by peptides selected to compete with the superantigen for its binding site in CD28. Superantigens use a conserved β-strand/hinge/α-helix domain of hitherto unknown function to engage CD28. Mutation of this superantigen domain abolished inflammatory cytokine gene induction and lethality. Structural analysis showed that when a superantigen binds to the T cell receptor on the T cell and major histocompatibility class II molecule on the antigen-presenting cell, CD28 can be accommodated readily as third superantigen receptor in the quaternary complex, with the CD28 dimer interface oriented towards the β-strand/hinge/α-helix domain in the superantigen. Our findings identify the CD28 homodimer interface as a critical receptor target for superantigens. The novel role of CD28 as receptor for a class of microbial pathogens, the superantigen toxins, broadens the scope of pathogen recognition mechanisms. Induction of protective immunity involves the expression of inflammatory cytokines, proteins that mediate and respond to immune signals. However, excessive cytokine induction can lead to disease, including, at very high levels, lethal toxic shock. Staphylococcal and streptococcal superantigens are a broad family of bacterial protein toxins that induce such a lethal cytokine storm, orders of magnitude higher in intensity than that elicited during normal immune responses. A key participant in every immune response is the costimulatory receptor CD28, which forms a protein dimer to mediate the immune response. Hitherto, CD28 was not known to bind microbial components. Here, we show that superantigens co-opt CD28 as their receptor and that to induce a cytokine storm, superantigens must bind directly into the dimer interface of CD28. The interaction between CD28 and the bacterial superantigen can be blocked with peptides—short protein fragments that mimic the contact domains in the intact superantigen or in CD28. These peptides attenuate inflammatory cytokine gene induction and thus protect animals from lethal toxic shock. Our finding that CD28 is a receptor for the superantigen toxins broadens the scope of microbial pathogen recognition mechanisms and provides a novel approach for designing therapeutics that protect against toxic shock.
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影响因子：
64.8
作者：
Fields, BA;Malchiodi, EL;Mariuzza, RA
通讯作者：
Mariuzza, RA
影响因子：
15.3
作者：
Proft, T;Moffatt, S L;Berkahn, C J;Fraser, J D
通讯作者：
Fraser, J D
DOI：
10.1084/jem.187.6.823
发表时间：
1998-03-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Leder L;Llera A;Lavoie PM;Lebedeva MI;Li H;Sékaly RP;Bohach GA;Gahr PJ;Schlievert PM;Karjalainen K;Mariuzza RA
通讯作者：
Mariuzza RA
影响因子：
4.4
作者：
Bhatia, S;Edidin, M;Nathenson, SG
通讯作者：
Nathenson, SG
DOI：
10.1073/pnas.84.23.8573
发表时间：
1987-12-01
影响因子：
11.1
作者：
ARUFFO, A;SEED, B
通讯作者：
SEED, B