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Interleukin-6 is crucial for recall of influenza-specific memory CD4 T cells.

Longhi MP, Wright K, Lauder SN, Nowell MA, Jones GW, Godkin AJ, Jones SA, Gallimore AM - PLoS Pathog. (2008)

Bottom Line: Specifically, we find that CD4+ but not CD8+ T cell memory is critically dependent upon IL-6.This effect of IL-6 includes its ability to suppress CD4+CD25+ regulatory T cells (Treg).We demonstrate that influenza-induced IL-6 limits the activity of virus-specific Tregs, thereby facilitating the activity of virus-specific memory CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.

ABSTRACT
Currently, our understanding of mechanisms underlying cell-mediated immunity and particularly of mechanisms that promote robust T cell memory to respiratory viruses is incomplete. Interleukin (IL)-6 has recently re-emerged as an important regulator of T cell proliferation and survival. Since IL-6 is abundant following infection with influenza virus, we analyzed virus-specific T cell activity in both wild type and IL-6 deficient mice. Studies outlined herein highlight a novel role for IL-6 in the development of T cell memory to influenza virus. Specifically, we find that CD4+ but not CD8+ T cell memory is critically dependent upon IL-6. This effect of IL-6 includes its ability to suppress CD4+CD25+ regulatory T cells (Treg). We demonstrate that influenza-induced IL-6 limits the activity of virus-specific Tregs, thereby facilitating the activity of virus-specific memory CD4+ T cells. These experiments reveal a critical role for IL-6 in ensuring, within the timeframe of an acute infection with a cytopathic virus, that antigen-specific Tregs have no opportunity to down-modulate the immune response, thereby favoring pathogen clearance and survival of the host.

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Related in: MedlinePlus

Nucleoprotein (NP)-Tetramer-positive CD8+ T cells in the spleens of influenza virus-infected mice.Representative dot plots showing staining of spleen cells recovered from a WT and IL-6−/− mouse 10 days post i.n. infection with 20 HAU H17 influenza virus. The cells were stained with CD8-specific mAbs and either the NP-Tetramer (Db-ASNENMDAM, NP-Tet) or an irrelevant tetramer comprising Db and a peptide derived from Lymphocytic choriomeningitis virus (Db-KAVYNFATC, GP-Tet). The plots are representative of 3 mice per group.
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ppat-1000006-g002: Nucleoprotein (NP)-Tetramer-positive CD8+ T cells in the spleens of influenza virus-infected mice.Representative dot plots showing staining of spleen cells recovered from a WT and IL-6−/− mouse 10 days post i.n. infection with 20 HAU H17 influenza virus. The cells were stained with CD8-specific mAbs and either the NP-Tetramer (Db-ASNENMDAM, NP-Tet) or an irrelevant tetramer comprising Db and a peptide derived from Lymphocytic choriomeningitis virus (Db-KAVYNFATC, GP-Tet). The plots are representative of 3 mice per group.

Mentions: To define the role IL-6 performs in orchestrating the immune response to viral infection, ex vivo studies tested whether IL-6 could affect primary and memory T cell responses to influenza infection. Firstly, CD8+ T cell activity was compared using cells derived from WT and IL6−/− mice following influenza virus infection. MHC class I tetramers comprising the Db-ASNENMDAM complex were used to stain lymphocytes recovered during the primary phase of the infection (day 10) and 8 weeks post-infection. The data shown in Figure 2 indicates that no significant difference was observed between the groups at day 10 post-infection whilst no tetramer positive cells were observed in either group following ex vivo staining of spleen cells 8 weeks post-infection (data not shown). Functional activity of these cells was assessed by CTL assay (Figure 3A and B) and again, no difference was observed in influenza-specific cytotoxic activity measured in spleen cells isolated from WT and IL-6−/− mice 2 and 8 weeks post-infection. The presence of CD8+ T cells in the lungs of both WT and IL-6−/− mice was also measured during days 2–12 of a primary (Figure 3C) and secondary infection with influenza virus (Figure 3D). A similar CD8+ T cell response was observed in the lungs of WT and IL-6−/− mice during the primary infection and following rechallenge with the same virus. Overall, these data indicate that lack of IL-6 had no significant effect on the generation or recall of the CD8+ T cell response to influenza virus.


Interleukin-6 is crucial for recall of influenza-specific memory CD4 T cells.

Longhi MP, Wright K, Lauder SN, Nowell MA, Jones GW, Godkin AJ, Jones SA, Gallimore AM - PLoS Pathog. (2008)

Nucleoprotein (NP)-Tetramer-positive CD8+ T cells in the spleens of influenza virus-infected mice.Representative dot plots showing staining of spleen cells recovered from a WT and IL-6−/− mouse 10 days post i.n. infection with 20 HAU H17 influenza virus. The cells were stained with CD8-specific mAbs and either the NP-Tetramer (Db-ASNENMDAM, NP-Tet) or an irrelevant tetramer comprising Db and a peptide derived from Lymphocytic choriomeningitis virus (Db-KAVYNFATC, GP-Tet). The plots are representative of 3 mice per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2279258&req=5

ppat-1000006-g002: Nucleoprotein (NP)-Tetramer-positive CD8+ T cells in the spleens of influenza virus-infected mice.Representative dot plots showing staining of spleen cells recovered from a WT and IL-6−/− mouse 10 days post i.n. infection with 20 HAU H17 influenza virus. The cells were stained with CD8-specific mAbs and either the NP-Tetramer (Db-ASNENMDAM, NP-Tet) or an irrelevant tetramer comprising Db and a peptide derived from Lymphocytic choriomeningitis virus (Db-KAVYNFATC, GP-Tet). The plots are representative of 3 mice per group.
Mentions: To define the role IL-6 performs in orchestrating the immune response to viral infection, ex vivo studies tested whether IL-6 could affect primary and memory T cell responses to influenza infection. Firstly, CD8+ T cell activity was compared using cells derived from WT and IL6−/− mice following influenza virus infection. MHC class I tetramers comprising the Db-ASNENMDAM complex were used to stain lymphocytes recovered during the primary phase of the infection (day 10) and 8 weeks post-infection. The data shown in Figure 2 indicates that no significant difference was observed between the groups at day 10 post-infection whilst no tetramer positive cells were observed in either group following ex vivo staining of spleen cells 8 weeks post-infection (data not shown). Functional activity of these cells was assessed by CTL assay (Figure 3A and B) and again, no difference was observed in influenza-specific cytotoxic activity measured in spleen cells isolated from WT and IL-6−/− mice 2 and 8 weeks post-infection. The presence of CD8+ T cells in the lungs of both WT and IL-6−/− mice was also measured during days 2–12 of a primary (Figure 3C) and secondary infection with influenza virus (Figure 3D). A similar CD8+ T cell response was observed in the lungs of WT and IL-6−/− mice during the primary infection and following rechallenge with the same virus. Overall, these data indicate that lack of IL-6 had no significant effect on the generation or recall of the CD8+ T cell response to influenza virus.

Bottom Line: Specifically, we find that CD4+ but not CD8+ T cell memory is critically dependent upon IL-6.This effect of IL-6 includes its ability to suppress CD4+CD25+ regulatory T cells (Treg).We demonstrate that influenza-induced IL-6 limits the activity of virus-specific Tregs, thereby facilitating the activity of virus-specific memory CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.

ABSTRACT
Currently, our understanding of mechanisms underlying cell-mediated immunity and particularly of mechanisms that promote robust T cell memory to respiratory viruses is incomplete. Interleukin (IL)-6 has recently re-emerged as an important regulator of T cell proliferation and survival. Since IL-6 is abundant following infection with influenza virus, we analyzed virus-specific T cell activity in both wild type and IL-6 deficient mice. Studies outlined herein highlight a novel role for IL-6 in the development of T cell memory to influenza virus. Specifically, we find that CD4+ but not CD8+ T cell memory is critically dependent upon IL-6. This effect of IL-6 includes its ability to suppress CD4+CD25+ regulatory T cells (Treg). We demonstrate that influenza-induced IL-6 limits the activity of virus-specific Tregs, thereby facilitating the activity of virus-specific memory CD4+ T cells. These experiments reveal a critical role for IL-6 in ensuring, within the timeframe of an acute infection with a cytopathic virus, that antigen-specific Tregs have no opportunity to down-modulate the immune response, thereby favoring pathogen clearance and survival of the host.

Show MeSH
Related in: MedlinePlus