The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling
Abstract Background The inflammatory 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 an...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-06-01
|
| Series: | Journal of Biomedical Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12929-023-00941-3 |
| _version_ | 1797789636078075904 |
|---|---|
| author | Andrey Popugailo Ziv Rotfogel Michal Levy Orli Turgeman Dalia Hillman Revital Levy Gila Arad Tomer Shpilka Raymond Kaempfer |
| author_facet | Andrey Popugailo Ziv Rotfogel Michal Levy Orli Turgeman Dalia Hillman Revital Levy Gila Arad Tomer Shpilka Raymond Kaempfer |
| author_sort | Andrey Popugailo |
| collection | DOAJ |
| description | Abstract Background The inflammatory 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 inflammatory 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 inflammatory 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 finding 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-inflammatory 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 inflammatory 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-inflammatory signaling via these receptor domains. |
| first_indexed | 2024-03-13T01:53:29Z |
| format | Article |
| id | doaj.art-72abed205b8b4743a7793760acc8aa32 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-03-13T01:53:29Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-72abed205b8b4743a7793760acc8aa322023-07-02T11:22:18ZengBMCJournal of Biomedical Science1423-01272023-06-0130111610.1186/s12929-023-00941-3The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signalingAndrey Popugailo0Ziv Rotfogel1Michal Levy2Orli Turgeman3Dalia Hillman4Revital Levy5Gila Arad6Tomer Shpilka7Raymond Kaempfer8Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical SchoolAbstract Background The inflammatory 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 inflammatory 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 inflammatory 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 finding 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-inflammatory 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 inflammatory 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-inflammatory signaling via these receptor domains.https://doi.org/10.1186/s12929-023-00941-3Inflammatory cytokine stormPro-inflammatory signalingCostimulatory receptors B7 and CD28Control of B7/CD28 receptor engagementReceptor homodimer interface mimetic peptidesRegulation of B7/CD28 signaling |
| spellingShingle | Andrey Popugailo Ziv Rotfogel Michal Levy Orli Turgeman Dalia Hillman Revital Levy Gila Arad Tomer Shpilka Raymond Kaempfer The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling Journal of Biomedical Science Inflammatory cytokine storm Pro-inflammatory signaling Costimulatory receptors B7 and CD28 Control of B7/CD28 receptor engagement Receptor homodimer interface mimetic peptides Regulation of B7/CD28 signaling |
| title | The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling |
| title_full | The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling |
| title_fullStr | The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling |
| title_full_unstemmed | The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling |
| title_short | The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling |
| title_sort | homodimer interfaces of costimulatory receptors b7 and cd28 control their engagement and pro inflammatory signaling |
| topic | Inflammatory cytokine storm Pro-inflammatory signaling Costimulatory receptors B7 and CD28 Control of B7/CD28 receptor engagement Receptor homodimer interface mimetic peptides Regulation of B7/CD28 signaling |
| url | https://doi.org/10.1186/s12929-023-00941-3 |
| work_keys_str_mv | AT andreypopugailo thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT zivrotfogel thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT michallevy thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT orliturgeman thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT daliahillman thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT revitallevy thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT gilaarad thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT tomershpilka thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT raymondkaempfer thehomodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT andreypopugailo homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT zivrotfogel homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT michallevy homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT orliturgeman homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT daliahillman homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT revitallevy homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT gilaarad homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT tomershpilka homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling AT raymondkaempfer homodimerinterfacesofcostimulatoryreceptorsb7andcd28controltheirengagementandproinflammatorysignaling |