The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.

Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells ha...

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Autores principales:	Anna Schurich, Laura J Pallett, Marcin Lubowiecki, Harsimran D Singh, Upkar S Gill, Patrick T Kennedy, Eleni Nastouli, Sudeep Tanwar, William Rosenberg, Mala K Maini
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ecbda8d131c8405d80876dbb21268402
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spelling	oai:doaj.org-article:ecbda8d131c8405d80876dbb212684022021-11-18T06:05:56ZThe third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.1553-73661553-737410.1371/journal.ppat.1003208https://doaj.org/article/ecbda8d131c8405d80876dbb212684022013-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23516358/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells has not been defined. We investigated the effect of using third signal cytokines IL-12 or IFN-α to rescue the exhausted CD8 T cell response characteristic of patients persistently infected with hepatitis B virus (HBV). We found that IL-12, but not IFN-α, potently augmented the capacity of HBV-specific CD8 T cells to produce effector cytokines upon stimulation by cognate antigen. Functional recovery mediated by IL-12 was accompanied by down-modulation of the hallmark inhibitory receptor PD-1 and an increase in the transcription factor T-bet. PD-1 down-regulation was observed in HBV but not CMV-specific T cells, in line with our finding that the highly functional CMV response was not further enhanced by IL-12. IL-12 enhanced a number of characteristics of HBV-specific T cells important for viral control: cytotoxicity, polyfunctionality and multispecificity. Furthermore, IL-12 significantly decreased the pro-apoptotic molecule Bim, which is capable of mediating premature attrition of HBV-specific CD8 T cells. Combining IL-12 with blockade of the PD-1 pathway further increased CD8 functionality in the majority of patients. These data provide new insights into the distinct signalling requirements of exhausted T cells and the potential to recover responses optimised to control persistent viral infections.Anna SchurichLaura J PallettMarcin LubowieckiHarsimran D SinghUpkar S GillPatrick T KennedyEleni NastouliSudeep TanwarWilliam RosenbergMala K MainiPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 3, p e1003208 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Anna Schurich Laura J Pallett Marcin Lubowiecki Harsimran D Singh Upkar S Gill Patrick T Kennedy Eleni Nastouli Sudeep Tanwar William Rosenberg Mala K Maini The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
description	Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells has not been defined. We investigated the effect of using third signal cytokines IL-12 or IFN-α to rescue the exhausted CD8 T cell response characteristic of patients persistently infected with hepatitis B virus (HBV). We found that IL-12, but not IFN-α, potently augmented the capacity of HBV-specific CD8 T cells to produce effector cytokines upon stimulation by cognate antigen. Functional recovery mediated by IL-12 was accompanied by down-modulation of the hallmark inhibitory receptor PD-1 and an increase in the transcription factor T-bet. PD-1 down-regulation was observed in HBV but not CMV-specific T cells, in line with our finding that the highly functional CMV response was not further enhanced by IL-12. IL-12 enhanced a number of characteristics of HBV-specific T cells important for viral control: cytotoxicity, polyfunctionality and multispecificity. Furthermore, IL-12 significantly decreased the pro-apoptotic molecule Bim, which is capable of mediating premature attrition of HBV-specific CD8 T cells. Combining IL-12 with blockade of the PD-1 pathway further increased CD8 functionality in the majority of patients. These data provide new insights into the distinct signalling requirements of exhausted T cells and the potential to recover responses optimised to control persistent viral infections.
format	article
author	Anna Schurich Laura J Pallett Marcin Lubowiecki Harsimran D Singh Upkar S Gill Patrick T Kennedy Eleni Nastouli Sudeep Tanwar William Rosenberg Mala K Maini
author_facet	Anna Schurich Laura J Pallett Marcin Lubowiecki Harsimran D Singh Upkar S Gill Patrick T Kennedy Eleni Nastouli Sudeep Tanwar William Rosenberg Mala K Maini
author_sort	Anna Schurich
title	The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
title_short	The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
title_full	The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
title_fullStr	The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
title_full_unstemmed	The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
title_sort	third signal cytokine il-12 rescues the anti-viral function of exhausted hbv-specific cd8 t cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/ecbda8d131c8405d80876dbb21268402
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The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.

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