The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant
Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73. Introduction
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Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73.
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European Commission Tomás-Cortázar, Julen Martín-Ruiz, Itziar Barriales, Diego Pascual-Itoiz, Miguel Ángel Gutiérrez de Juan, Virginia Caro-Maldonado, Alfredo Merino, Nekane Marina, Alberto Blanco, Francisco J. Flores, Juana María Sutherland, James D. Barrio, Rosa Rojas, Adriana Martínez-Chantar, María Luz Carracedo, Arkaitz Simó, Carolina García-Cañas, Virginia Abecia, Leticia Lavín, José Luis Aransay, Ana M. Rodríguez, Héctor Anguita, Juan |
format |
artículo |
author |
Tomás-Cortázar, Julen Martín-Ruiz, Itziar Barriales, Diego Pascual-Itoiz, Miguel Ángel Gutiérrez de Juan, Virginia Caro-Maldonado, Alfredo Merino, Nekane Marina, Alberto Blanco, Francisco J. Flores, Juana María Sutherland, James D. Barrio, Rosa Rojas, Adriana Martínez-Chantar, María Luz Carracedo, Arkaitz Simó, Carolina García-Cañas, Virginia Abecia, Leticia Lavín, José Luis Aransay, Ana M. Rodríguez, Héctor Anguita, Juan |
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Tomás-Cortázar, Julen Martín-Ruiz, Itziar Barriales, Diego Pascual-Itoiz, Miguel Ángel Gutiérrez de Juan, Virginia Caro-Maldonado, Alfredo Merino, Nekane Marina, Alberto Blanco, Francisco J. Flores, Juana María Sutherland, James D. Barrio, Rosa Rojas, Adriana Martínez-Chantar, María Luz Carracedo, Arkaitz Simó, Carolina García-Cañas, Virginia Abecia, Leticia Lavín, José Luis Aransay, Ana M. Rodríguez, Héctor Anguita, Juan The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant |
author_sort |
Tomás-Cortázar, Julen |
title |
The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant |
title_short |
The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant |
title_full |
The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant |
title_fullStr |
The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant |
title_full_unstemmed |
The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant |
title_sort |
immunosuppressive effect of the tick protein, salp15, is long-lasting and persists in a murine model of hematopoietic transplant |
publisher |
Springer Nature |
publishDate |
2017 |
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http://hdl.handle.net/10261/194249 http://dx.doi.org/10.13039/501100004587 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/501100000781 http://dx.doi.org/10.13039/501100003086 |
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dig-cial-es-10261-1942492021-12-27T15:56:45Z The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant Tomás-Cortázar, Julen Martín-Ruiz, Itziar Barriales, Diego Pascual-Itoiz, Miguel Ángel Gutiérrez de Juan, Virginia Caro-Maldonado, Alfredo Merino, Nekane Marina, Alberto Blanco, Francisco J. Flores, Juana María Sutherland, James D. Barrio, Rosa Rojas, Adriana Martínez-Chantar, María Luz Carracedo, Arkaitz Simó, Carolina García-Cañas, Virginia Abecia, Leticia Lavín, José Luis Aransay, Ana M. Rodríguez, Héctor Anguita, Juan European Commission Eusko Jaurlaritza Ministerio de Economía y Competitividad (España) Instituto de Salud Carlos III European Research Council Barriales, Diego [0000-0002-6433-3379] Blanco, Francisco J. [0000-0003-2545-4319] Sutherland, James D. [0000-0003-3229-793X] Barrio, Rosa [0000-0002-9663-0669] Rojas, Adriana [0000-0002-7358-3505] Carracedo, Arkaitz [0000-0001-5957-1260] Abecia, L. [0000-0003-4097-8903] Aransay, Ana M. [0000-0002-8271-612X] Anguita, Juan [0000-0003-2061-7182] Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73. Introduction Supported by grants from the Department of Education of the Basque Government (PI2013-49 to JA and PI2012-42 to RB). JA is funded by the European Union (Grant Agreement number 602272). AMA and JLL’s work was supported by the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek Programs), the Innovation Technology Department of Bizkaia and the CIBERehd Network. The work of AC is supported by a Ramón y Cajal award, the Basque Department of Industry, Tourism and Trade (Etortek), ISCIII (PI13/00031), FERO VIII Fellowship, the BBVA foundation, MINECO (SAF2016-79381-R) and the European Research Council Starting Grant (336343). CIBERonc was co-funded with FEDER funds. AC-M was funded by a Juan de la Cierva program award and the European Union MSCA program (CIG 660191). RB was funded by MINECO grants BFU2011-25986 and BFU2014-52282-P and the Consolider Program (BFU2014-57703-REDC). FJB was funded by a MINECO grant (CTQ2014-56966-R). D.B. is funded by a MINECO FPI fellowship. We thank the MINECO for the Severo Ochoa Excellence accreditation (SEV-2016-0644). Peer reviewed 2019-11-11T08:22:29Z 2019-11-11T08:22:29Z 2017 artículo http://purl.org/coar/resource_type/c_6501 Scientific Reports 7: 10740 (2017) http://hdl.handle.net/10261/194249 10.1038/s41598-017-11354-2 2045-2322 http://dx.doi.org/10.13039/501100004587 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/501100000781 http://dx.doi.org/10.13039/501100003086 28878331 en #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/EC/FP7/602272 info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-79381-R info:eu-repo/grantAgreement/EC/FP7/336343 info:eu-repo/grantAgreement/EC/H2020/660191 info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014-52282-P info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014-57703-REDC info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2014-56966-R info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SEV-2016-0644 Publisher's version https://doi.org/10.1038/s41598-017-11354-2 Sí open Springer Nature |