- 作者: Andrey Popugailo, Ziv Rotfogel, Michal Levy, Orli Turgeman, Dalia Hillman, Revital Levy, Gila Arad, Tomer Shpilka & Raymond Kaempfer
- 作者服務機構: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102, Jerusalem, Israel
- 中文摘要:
- 英文摘要:
Background The infammatory response is indispensable for protective immunity, yet microbial pathogens often
trigger an excessive response, ‘cytokine storm’, harmful to the host. Full T-cell activation requires interaction of costimulatory receptors B7-1(CD80) and B7-2(CD86) expressed on antigen-presenting cells with CD28 expressed on the T
cells. We created short peptide mimetics of the homodimer interfaces of the B7 and CD28 receptors and examined
their ability to attenuate B7/CD28 coligand engagement and signaling through CD28 for infammatory cytokine
induction in human immune cells, and to protect from lethal toxic shock in vivo.
Methods Short B7 and CD28 receptor dimer interface mimetic peptides were synthesized and tested for their ability
to attenuate the infammatory cytokine response of human peripheral blood mononuclear cells, as well as for their
ability to attenuate B7/CD28 intercellular receptor engagement. Mice were used to test the ability of such peptides to
protect from lethal superantigen toxin challenge when administered in molar doses far below the toxin dose.
Results B7 and CD28 homodimer interfaces are remote from the coligand binding sites, yet our fnding is that by
binding back into the receptor dimer interfaces, short dimer interface mimetic peptides inhibit intercellular B7-2/
CD28 as well as the tighter B7-1/CD28 engagement, attenuating thereby pro-infammatory signaling. B7 mimetic
peptides exhibit tight selectivity for the cognate receptor in inhibiting intercellular receptor engagement with CD28,
yet each diminishes signaling through CD28. In a prominent example of infammatory cytokine storm, by attenuating formation of the B7/CD28 costimulatory axis, B7-1 and CD28 dimer interface mimetic peptides protect mice
from lethal toxic shock induced by a bacterial superantigen even when administered in doses far submolar to the
superantigen.
Conclusions Our results reveal that the B7 and CD28 homodimer interfaces each control B7/CD28 costimulatory
receptor engagement and highlight the protective potential against cytokine storm of attenuating, yet not ablating,
pro-infammatory signaling via these receptor domains. - 中文關鍵字:
- 英文關鍵字: Infammatory cytokine storm, Pro-infammatory signaling, Costimulatory receptors B7 and CD28, Control of B7/CD28 receptor engagement, Receptor homodimer interface mimetic peptides, Regulation of B7/CD28 signaling