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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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Related in: MedlinePlus

TIM-3 expression is up regulated on virus-specific CD8+ T cells after HSV infection.C57BL/6 animals were infected in each hind footpad with 2.5×105 PFU of HSV. At different time points after infection, draining popliteal LNs (PLNs) cells isolated from three animals at each time point were analyzed flow cytometrically for TIM-3, Kb-gB-tetramer and IFN-γ staining. A. FACS plots showing the frequencies of TIM-3+ (upper panel), Kb-gB-Tet+ (middle panel) and SSIEFRAL-peptide stimulated IFN-γ producing (lower panel) CD8+ T cells are shown. Percentages (B) and absolute numbers (C) of TIM-3+, Kb-gB-Tet+ and SSIEFRAL-peptide stimulated IFN-γ producing CD8+ T cells in the draining PLN of HSV infected animals are shown. D. Co-expression of TIM-3 (upper panel) and Kb-gB-Tet (lower panel) with CD44 and CD62L is shown by representative FACS plots. E. FACS plots showing IFN-γ production by TIM-3+ (upper panel) and Kb-gB-Tet+ expression by TIM-3+CD8+ T cells are shown. F. Representative FACS plots show TIM-3 expression on Kb-gB-Tet+ (upper panel) and IFN-γ+CD8+ T (lower panel) cells G. FACS plots show the expression of TIM-3 (upper panel) and KLRG1 (lower panel) on IFN-γ producing CD8+ T cells.
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ppat-1000882-g001: TIM-3 expression is up regulated on virus-specific CD8+ T cells after HSV infection.C57BL/6 animals were infected in each hind footpad with 2.5×105 PFU of HSV. At different time points after infection, draining popliteal LNs (PLNs) cells isolated from three animals at each time point were analyzed flow cytometrically for TIM-3, Kb-gB-tetramer and IFN-γ staining. A. FACS plots showing the frequencies of TIM-3+ (upper panel), Kb-gB-Tet+ (middle panel) and SSIEFRAL-peptide stimulated IFN-γ producing (lower panel) CD8+ T cells are shown. Percentages (B) and absolute numbers (C) of TIM-3+, Kb-gB-Tet+ and SSIEFRAL-peptide stimulated IFN-γ producing CD8+ T cells in the draining PLN of HSV infected animals are shown. D. Co-expression of TIM-3 (upper panel) and Kb-gB-Tet (lower panel) with CD44 and CD62L is shown by representative FACS plots. E. FACS plots showing IFN-γ production by TIM-3+ (upper panel) and Kb-gB-Tet+ expression by TIM-3+CD8+ T cells are shown. F. Representative FACS plots show TIM-3 expression on Kb-gB-Tet+ (upper panel) and IFN-γ+CD8+ T (lower panel) cells G. FACS plots show the expression of TIM-3 (upper panel) and KLRG1 (lower panel) on IFN-γ producing CD8+ T cells.

Mentions: CD8+ T cells isolated from the draining popliteal LNs (PLN) and spleens of HSV infected animals were analyzed for TIM-3 expression at different times pi. As is evident in Fig 1A, whereas few CD8+ T cells isolated from LNs of uninfected animals expressed TIM-3, after HSV infection TIM-3+ cells were numerous. This increase in TIM-3+CD8+ T cells was evident at day 3 pi in the PLN and day 4 in the spleen (Figure S1) and peak frequencies (Fig 1A and B), as well as total numbers (Fig 1C), were present on days 6. The majority of TIM-3+ T cells isolated from infected animals were CD44hi and CD62Llo suggesting that only activated or effector T cells expressed surface TIM-3+ (Fig 1D).


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)

TIM-3 expression is up regulated on virus-specific CD8+ T cells after HSV infection.C57BL/6 animals were infected in each hind footpad with 2.5×105 PFU of HSV. At different time points after infection, draining popliteal LNs (PLNs) cells isolated from three animals at each time point were analyzed flow cytometrically for TIM-3, Kb-gB-tetramer and IFN-γ staining. A. FACS plots showing the frequencies of TIM-3+ (upper panel), Kb-gB-Tet+ (middle panel) and SSIEFRAL-peptide stimulated IFN-γ producing (lower panel) CD8+ T cells are shown. Percentages (B) and absolute numbers (C) of TIM-3+, Kb-gB-Tet+ and SSIEFRAL-peptide stimulated IFN-γ producing CD8+ T cells in the draining PLN of HSV infected animals are shown. D. Co-expression of TIM-3 (upper panel) and Kb-gB-Tet (lower panel) with CD44 and CD62L is shown by representative FACS plots. E. FACS plots showing IFN-γ production by TIM-3+ (upper panel) and Kb-gB-Tet+ expression by TIM-3+CD8+ T cells are shown. F. Representative FACS plots show TIM-3 expression on Kb-gB-Tet+ (upper panel) and IFN-γ+CD8+ T (lower panel) cells G. FACS plots show the expression of TIM-3 (upper panel) and KLRG1 (lower panel) on IFN-γ producing CD8+ T cells.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2865527&req=5

ppat-1000882-g001: TIM-3 expression is up regulated on virus-specific CD8+ T cells after HSV infection.C57BL/6 animals were infected in each hind footpad with 2.5×105 PFU of HSV. At different time points after infection, draining popliteal LNs (PLNs) cells isolated from three animals at each time point were analyzed flow cytometrically for TIM-3, Kb-gB-tetramer and IFN-γ staining. A. FACS plots showing the frequencies of TIM-3+ (upper panel), Kb-gB-Tet+ (middle panel) and SSIEFRAL-peptide stimulated IFN-γ producing (lower panel) CD8+ T cells are shown. Percentages (B) and absolute numbers (C) of TIM-3+, Kb-gB-Tet+ and SSIEFRAL-peptide stimulated IFN-γ producing CD8+ T cells in the draining PLN of HSV infected animals are shown. D. Co-expression of TIM-3 (upper panel) and Kb-gB-Tet (lower panel) with CD44 and CD62L is shown by representative FACS plots. E. FACS plots showing IFN-γ production by TIM-3+ (upper panel) and Kb-gB-Tet+ expression by TIM-3+CD8+ T cells are shown. F. Representative FACS plots show TIM-3 expression on Kb-gB-Tet+ (upper panel) and IFN-γ+CD8+ T (lower panel) cells G. FACS plots show the expression of TIM-3 (upper panel) and KLRG1 (lower panel) on IFN-γ producing CD8+ T cells.
Mentions: CD8+ T cells isolated from the draining popliteal LNs (PLN) and spleens of HSV infected animals were analyzed for TIM-3 expression at different times pi. As is evident in Fig 1A, whereas few CD8+ T cells isolated from LNs of uninfected animals expressed TIM-3, after HSV infection TIM-3+ cells were numerous. This increase in TIM-3+CD8+ T cells was evident at day 3 pi in the PLN and day 4 in the spleen (Figure S1) and peak frequencies (Fig 1A and B), as well as total numbers (Fig 1C), were present on days 6. The majority of TIM-3+ T cells isolated from infected animals were CD44hi and CD62Llo suggesting that only activated or effector T cells expressed surface TIM-3+ (Fig 1D).

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