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Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response.

Sehrawat S, Reddy PB, Rajasagi N, Suryawanshi A, Hirashima M, Rouse BT - PLoS Pathog. (2010)

Bottom Line: In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals.The increased effector T cell responses led to significantly more efficient virus control.Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA.

ABSTRACT
In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8(+) T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with alpha-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8(+) T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8(+) T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3(+) CD8(+) T effector cells as well as the promotion of Foxp3(+) regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.

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Galectin-9 KO animals develop sustained virus-specific CD8+ T cells memory responses.The lymphoid organs of HSV infected WT and Gal-9 KO animals were analyzed at day 32 or day 60 after infection for early and long-term memory responses using Kb-gB-tetramer and ICCS assays. All but long term memory experiments were repeated at least three times with four animals per group. A. Representative FACS plots showing the frequencies of Kb-gB-Tet+ cells in the spleens of WT and Gal-9 KO animals at 60 dpi. B. Representative FACS plots showing the frequencies of SSIEFARL peptide stimulated IFN-γ and TNF-α producing CD8+ T cells at 60 dpi. C. Bar diagram show the absolute numbers of Kb-gB-Tet+ and IFN-γ producing CD8+ T cells in the spleens of WT and Gal-9 KO animals as depicted by FACS plots in A and B at day 60. D. The bar diagram shows the ratio of SSIEFARL stimulated IFN-γ+TNF-α+ to IFN-γ+ CD8+ T cells isolated from WT and Gal-9 KO mice at 60 dpi. E-J. The animals previously infected with HSV for 32 days were re-infected with the same dose of HSV in footpads and the virus-specific CD8+ T cells responses were quantified in the PLN 2.5 dpi. E. Representative FACS plots show the frequencies of Kb-gB-Tet+ CD8+ T cells in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. F. Representative FACS plots show the frequencies of SSIFERAL-stimulated IFN-γ and TNF-α producing CD8+ T cell in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. G-H. The bar diagram shows the frequencies (G) and numbers (H) of Kb-gB-Tet+ and cytokines producing CD8+ T cells as depicted by FACS plots in E and F. I. MFI of cytokines produced by stimulated CD8+ T cell is shown. J. The peptide-specific proliferative response of PLNs cells isolated from re-infected animals at 2.5dpi is shown.
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ppat-1000882-g005: Galectin-9 KO animals develop sustained virus-specific CD8+ T cells memory responses.The lymphoid organs of HSV infected WT and Gal-9 KO animals were analyzed at day 32 or day 60 after infection for early and long-term memory responses using Kb-gB-tetramer and ICCS assays. All but long term memory experiments were repeated at least three times with four animals per group. A. Representative FACS plots showing the frequencies of Kb-gB-Tet+ cells in the spleens of WT and Gal-9 KO animals at 60 dpi. B. Representative FACS plots showing the frequencies of SSIEFARL peptide stimulated IFN-γ and TNF-α producing CD8+ T cells at 60 dpi. C. Bar diagram show the absolute numbers of Kb-gB-Tet+ and IFN-γ producing CD8+ T cells in the spleens of WT and Gal-9 KO animals as depicted by FACS plots in A and B at day 60. D. The bar diagram shows the ratio of SSIEFARL stimulated IFN-γ+TNF-α+ to IFN-γ+ CD8+ T cells isolated from WT and Gal-9 KO mice at 60 dpi. E-J. The animals previously infected with HSV for 32 days were re-infected with the same dose of HSV in footpads and the virus-specific CD8+ T cells responses were quantified in the PLN 2.5 dpi. E. Representative FACS plots show the frequencies of Kb-gB-Tet+ CD8+ T cells in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. F. Representative FACS plots show the frequencies of SSIFERAL-stimulated IFN-γ and TNF-α producing CD8+ T cell in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. G-H. The bar diagram shows the frequencies (G) and numbers (H) of Kb-gB-Tet+ and cytokines producing CD8+ T cells as depicted by FACS plots in E and F. I. MFI of cytokines produced by stimulated CD8+ T cell is shown. J. The peptide-specific proliferative response of PLNs cells isolated from re-infected animals at 2.5dpi is shown.

Mentions: Comparisons of the magnitude and quality of HSV specific CD8+ T cell responses of Gal-9 KO and WT animals were also made 32 and 60 days pi to record memory phase effects. The results of a sample experiment, done at 60 days pi, are recorded in Fig 5. As in the acute phase, the memory responses of Gal-9 animals exceeded those of WT animals. Thus, the frequencies (Fig 5A) and total numbers (Fig 5C) of CD8+ and Kb-gB Tet+ T cells were increased by approximately 2.5 fold in Gal-9 KO, as compared to those of WT animals. In addition, the frequency and numbers of peptide-specific CD8+ T cells that produced both IFN-γ and TNF-α cytokines was also significantly higher in the spleens of Gal-9 KO population than in WT (Fig 5B-D) indicative of higher quality memory responses. Accordingly, in the absence of Gal-9, memory CD8+ T cell responses to HSV were increased.


Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response.

Sehrawat S, Reddy PB, Rajasagi N, Suryawanshi A, Hirashima M, Rouse BT - PLoS Pathog. (2010)

Galectin-9 KO animals develop sustained virus-specific CD8+ T cells memory responses.The lymphoid organs of HSV infected WT and Gal-9 KO animals were analyzed at day 32 or day 60 after infection for early and long-term memory responses using Kb-gB-tetramer and ICCS assays. All but long term memory experiments were repeated at least three times with four animals per group. A. Representative FACS plots showing the frequencies of Kb-gB-Tet+ cells in the spleens of WT and Gal-9 KO animals at 60 dpi. B. Representative FACS plots showing the frequencies of SSIEFARL peptide stimulated IFN-γ and TNF-α producing CD8+ T cells at 60 dpi. C. Bar diagram show the absolute numbers of Kb-gB-Tet+ and IFN-γ producing CD8+ T cells in the spleens of WT and Gal-9 KO animals as depicted by FACS plots in A and B at day 60. D. The bar diagram shows the ratio of SSIEFARL stimulated IFN-γ+TNF-α+ to IFN-γ+ CD8+ T cells isolated from WT and Gal-9 KO mice at 60 dpi. E-J. The animals previously infected with HSV for 32 days were re-infected with the same dose of HSV in footpads and the virus-specific CD8+ T cells responses were quantified in the PLN 2.5 dpi. E. Representative FACS plots show the frequencies of Kb-gB-Tet+ CD8+ T cells in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. F. Representative FACS plots show the frequencies of SSIFERAL-stimulated IFN-γ and TNF-α producing CD8+ T cell in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. G-H. The bar diagram shows the frequencies (G) and numbers (H) of Kb-gB-Tet+ and cytokines producing CD8+ T cells as depicted by FACS plots in E and F. I. MFI of cytokines produced by stimulated CD8+ T cell is shown. J. The peptide-specific proliferative response of PLNs cells isolated from re-infected animals at 2.5dpi is shown.
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ppat-1000882-g005: Galectin-9 KO animals develop sustained virus-specific CD8+ T cells memory responses.The lymphoid organs of HSV infected WT and Gal-9 KO animals were analyzed at day 32 or day 60 after infection for early and long-term memory responses using Kb-gB-tetramer and ICCS assays. All but long term memory experiments were repeated at least three times with four animals per group. A. Representative FACS plots showing the frequencies of Kb-gB-Tet+ cells in the spleens of WT and Gal-9 KO animals at 60 dpi. B. Representative FACS plots showing the frequencies of SSIEFARL peptide stimulated IFN-γ and TNF-α producing CD8+ T cells at 60 dpi. C. Bar diagram show the absolute numbers of Kb-gB-Tet+ and IFN-γ producing CD8+ T cells in the spleens of WT and Gal-9 KO animals as depicted by FACS plots in A and B at day 60. D. The bar diagram shows the ratio of SSIEFARL stimulated IFN-γ+TNF-α+ to IFN-γ+ CD8+ T cells isolated from WT and Gal-9 KO mice at 60 dpi. E-J. The animals previously infected with HSV for 32 days were re-infected with the same dose of HSV in footpads and the virus-specific CD8+ T cells responses were quantified in the PLN 2.5 dpi. E. Representative FACS plots show the frequencies of Kb-gB-Tet+ CD8+ T cells in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. F. Representative FACS plots show the frequencies of SSIFERAL-stimulated IFN-γ and TNF-α producing CD8+ T cell in the PLNs of WT (n = 4) and Gal-9 KO (n = 4) animals. G-H. The bar diagram shows the frequencies (G) and numbers (H) of Kb-gB-Tet+ and cytokines producing CD8+ T cells as depicted by FACS plots in E and F. I. MFI of cytokines produced by stimulated CD8+ T cell is shown. J. The peptide-specific proliferative response of PLNs cells isolated from re-infected animals at 2.5dpi is shown.
Mentions: Comparisons of the magnitude and quality of HSV specific CD8+ T cell responses of Gal-9 KO and WT animals were also made 32 and 60 days pi to record memory phase effects. The results of a sample experiment, done at 60 days pi, are recorded in Fig 5. As in the acute phase, the memory responses of Gal-9 animals exceeded those of WT animals. Thus, the frequencies (Fig 5A) and total numbers (Fig 5C) of CD8+ and Kb-gB Tet+ T cells were increased by approximately 2.5 fold in Gal-9 KO, as compared to those of WT animals. In addition, the frequency and numbers of peptide-specific CD8+ T cells that produced both IFN-γ and TNF-α cytokines was also significantly higher in the spleens of Gal-9 KO population than in WT (Fig 5B-D) indicative of higher quality memory responses. Accordingly, in the absence of Gal-9, memory CD8+ T cell responses to HSV were increased.

Bottom Line: In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals.The increased effector T cell responses led to significantly more efficient virus control.Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA.

ABSTRACT
In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8(+) T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with alpha-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8(+) T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8(+) T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3(+) CD8(+) T effector cells as well as the promotion of Foxp3(+) regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.

Show MeSH
Related in: MedlinePlus