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Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria.

Stephens R, Langhorne J - PLoS Pathog. (2010)

Bottom Line: CD4(+) memory T cells (CD44(hi)IL-7Rα(+)) developed during the chronic infection, and were readily distinguishable from effector (CD62L(lo)IL-7Rα(-)) cells in acute infection.On the basis of cell surface phenotype, we classified memory CD4(+) T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62L(lo)CD27(+)) dominated the chronic infection.We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells.

View Article: PubMed Central - PubMed

Affiliation: MRC National Institute for Medical Research, London, UK.

ABSTRACT
Protection against malaria often decays in the absence of infection, suggesting that protective immunological memory depends on stimulation. Here we have used CD4(+) T cells from a transgenic mouse carrying a T cell receptor specific for a malaria protein, Merozoite Surface Protein-1, to investigate memory in a Plasmodium chabaudi infection. CD4(+) memory T cells (CD44(hi)IL-7Rα(+)) developed during the chronic infection, and were readily distinguishable from effector (CD62L(lo)IL-7Rα(-)) cells in acute infection. On the basis of cell surface phenotype, we classified memory CD4(+) T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62L(lo)CD27(+)) dominated the chronic infection. We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells. In adoptive transfer, CD44(hi) memory cells from chronically infected mice were more effective at delaying and reducing parasitemia and pathology than memory cells from drug-treated mice without chronic infection, and contained a greater proportion of effector cells producing IFN-γ and TNFα, which may have contributed to the enhanced protection. These findings may explain the observation that in humans with chronic malaria, activated effector memory cells are best maintained in conditions of repeated exposure.

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Treatment of a chronic P. chabaudi infection changes the phenotype of memory cells and their cytokine profiles towards Th1 late effector profile.CD4+ MSP1-specific B5 Tg T cells were seeded into Thy1.1 congenic mice to follow the antigen-specific response. Mice were infected with 105 Plasmodium chabaudi and treated with Chloroquine (CQ) during days 30–34 to clear the chronic infection. Splenocytes were analyzed by flow cytometry on day 60 post-infection, and the FACS plots were gated on Thy1.2+CD4+ cells. A) Differences in the proportions of Tmem, (CD44hi IL-7Rα+), and effector (Teff, CD44hi IL-7Rα−) cells at day 60 between mice treated and not treated with chloroquine (+CQ and −CQ respectively). The percentage of IL-7Rα+ Tmem or IL-7Rα− Teff within the CD44hi cell population is shown as a graph (right). These differences were observed in 4 independent experiments. B) IFN-γ and TNFα production in Thy1.2+CD4+ CD44hiCD62Llo B5 cells from chloroquine-treated and -untreated mice at day 60 post infection. C) Multiple cytokine producing B5 CD4 T cells from chloroquine-treated and untreated mice at day 60 post-infection. Percent double-producing TNFα+IFN-γ+IL-2− and triple-producing IFN-γ+TNFα+IL-2+ are shown. D) IFNγ+ TNFα+ (IL-2−) double producing cells within the Tem subset of B5 at 60 days post-infection. The graphs show means and SEM from 5 mice. ** p≤.01 and * p≤.05 by student's t-test.
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ppat-1001208-g005: Treatment of a chronic P. chabaudi infection changes the phenotype of memory cells and their cytokine profiles towards Th1 late effector profile.CD4+ MSP1-specific B5 Tg T cells were seeded into Thy1.1 congenic mice to follow the antigen-specific response. Mice were infected with 105 Plasmodium chabaudi and treated with Chloroquine (CQ) during days 30–34 to clear the chronic infection. Splenocytes were analyzed by flow cytometry on day 60 post-infection, and the FACS plots were gated on Thy1.2+CD4+ cells. A) Differences in the proportions of Tmem, (CD44hi IL-7Rα+), and effector (Teff, CD44hi IL-7Rα−) cells at day 60 between mice treated and not treated with chloroquine (+CQ and −CQ respectively). The percentage of IL-7Rα+ Tmem or IL-7Rα− Teff within the CD44hi cell population is shown as a graph (right). These differences were observed in 4 independent experiments. B) IFN-γ and TNFα production in Thy1.2+CD4+ CD44hiCD62Llo B5 cells from chloroquine-treated and -untreated mice at day 60 post infection. C) Multiple cytokine producing B5 CD4 T cells from chloroquine-treated and untreated mice at day 60 post-infection. Percent double-producing TNFα+IFN-γ+IL-2− and triple-producing IFN-γ+TNFα+IL-2+ are shown. D) IFNγ+ TNFα+ (IL-2−) double producing cells within the Tem subset of B5 at 60 days post-infection. The graphs show means and SEM from 5 mice. ** p≤.01 and * p≤.05 by student's t-test.

Mentions: In line with the more rapid effect on parasitemia after adoptive transfer, there was a larger population of IL-7Rα− effector T cells (Teff) in the chronically infected mice (Figure 5A, p = 0.038) compared with CQ-treated mice. Conversely, there was a significantly greater proportion of IL-7Rα+CD44hi memory T cells in the B5 CD4+ T cell population from CQ-treated mice (+CQ, Figure 5A, p = 0.0073). The increase of effector cells in chronically infected mice and the decrease in memory T cells was also seen in the endogenous CD4+ population (Figure S8). We could not detect any reproducible differences in the activation markers of effector cells (as defined in Figure 1) between chronically stimulated and “rested” memory Tg CD4 T cells, nor in the composition of the memory cell subsets (as defined in Figure 2C).


Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria.

Stephens R, Langhorne J - PLoS Pathog. (2010)

Treatment of a chronic P. chabaudi infection changes the phenotype of memory cells and their cytokine profiles towards Th1 late effector profile.CD4+ MSP1-specific B5 Tg T cells were seeded into Thy1.1 congenic mice to follow the antigen-specific response. Mice were infected with 105 Plasmodium chabaudi and treated with Chloroquine (CQ) during days 30–34 to clear the chronic infection. Splenocytes were analyzed by flow cytometry on day 60 post-infection, and the FACS plots were gated on Thy1.2+CD4+ cells. A) Differences in the proportions of Tmem, (CD44hi IL-7Rα+), and effector (Teff, CD44hi IL-7Rα−) cells at day 60 between mice treated and not treated with chloroquine (+CQ and −CQ respectively). The percentage of IL-7Rα+ Tmem or IL-7Rα− Teff within the CD44hi cell population is shown as a graph (right). These differences were observed in 4 independent experiments. B) IFN-γ and TNFα production in Thy1.2+CD4+ CD44hiCD62Llo B5 cells from chloroquine-treated and -untreated mice at day 60 post infection. C) Multiple cytokine producing B5 CD4 T cells from chloroquine-treated and untreated mice at day 60 post-infection. Percent double-producing TNFα+IFN-γ+IL-2− and triple-producing IFN-γ+TNFα+IL-2+ are shown. D) IFNγ+ TNFα+ (IL-2−) double producing cells within the Tem subset of B5 at 60 days post-infection. The graphs show means and SEM from 5 mice. ** p≤.01 and * p≤.05 by student's t-test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991260&req=5

ppat-1001208-g005: Treatment of a chronic P. chabaudi infection changes the phenotype of memory cells and their cytokine profiles towards Th1 late effector profile.CD4+ MSP1-specific B5 Tg T cells were seeded into Thy1.1 congenic mice to follow the antigen-specific response. Mice were infected with 105 Plasmodium chabaudi and treated with Chloroquine (CQ) during days 30–34 to clear the chronic infection. Splenocytes were analyzed by flow cytometry on day 60 post-infection, and the FACS plots were gated on Thy1.2+CD4+ cells. A) Differences in the proportions of Tmem, (CD44hi IL-7Rα+), and effector (Teff, CD44hi IL-7Rα−) cells at day 60 between mice treated and not treated with chloroquine (+CQ and −CQ respectively). The percentage of IL-7Rα+ Tmem or IL-7Rα− Teff within the CD44hi cell population is shown as a graph (right). These differences were observed in 4 independent experiments. B) IFN-γ and TNFα production in Thy1.2+CD4+ CD44hiCD62Llo B5 cells from chloroquine-treated and -untreated mice at day 60 post infection. C) Multiple cytokine producing B5 CD4 T cells from chloroquine-treated and untreated mice at day 60 post-infection. Percent double-producing TNFα+IFN-γ+IL-2− and triple-producing IFN-γ+TNFα+IL-2+ are shown. D) IFNγ+ TNFα+ (IL-2−) double producing cells within the Tem subset of B5 at 60 days post-infection. The graphs show means and SEM from 5 mice. ** p≤.01 and * p≤.05 by student's t-test.
Mentions: In line with the more rapid effect on parasitemia after adoptive transfer, there was a larger population of IL-7Rα− effector T cells (Teff) in the chronically infected mice (Figure 5A, p = 0.038) compared with CQ-treated mice. Conversely, there was a significantly greater proportion of IL-7Rα+CD44hi memory T cells in the B5 CD4+ T cell population from CQ-treated mice (+CQ, Figure 5A, p = 0.0073). The increase of effector cells in chronically infected mice and the decrease in memory T cells was also seen in the endogenous CD4+ population (Figure S8). We could not detect any reproducible differences in the activation markers of effector cells (as defined in Figure 1) between chronically stimulated and “rested” memory Tg CD4 T cells, nor in the composition of the memory cell subsets (as defined in Figure 2C).

Bottom Line: CD4(+) memory T cells (CD44(hi)IL-7Rα(+)) developed during the chronic infection, and were readily distinguishable from effector (CD62L(lo)IL-7Rα(-)) cells in acute infection.On the basis of cell surface phenotype, we classified memory CD4(+) T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62L(lo)CD27(+)) dominated the chronic infection.We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells.

View Article: PubMed Central - PubMed

Affiliation: MRC National Institute for Medical Research, London, UK.

ABSTRACT
Protection against malaria often decays in the absence of infection, suggesting that protective immunological memory depends on stimulation. Here we have used CD4(+) T cells from a transgenic mouse carrying a T cell receptor specific for a malaria protein, Merozoite Surface Protein-1, to investigate memory in a Plasmodium chabaudi infection. CD4(+) memory T cells (CD44(hi)IL-7Rα(+)) developed during the chronic infection, and were readily distinguishable from effector (CD62L(lo)IL-7Rα(-)) cells in acute infection. On the basis of cell surface phenotype, we classified memory CD4(+) T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62L(lo)CD27(+)) dominated the chronic infection. We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells. In adoptive transfer, CD44(hi) memory cells from chronically infected mice were more effective at delaying and reducing parasitemia and pathology than memory cells from drug-treated mice without chronic infection, and contained a greater proportion of effector cells producing IFN-γ and TNFα, which may have contributed to the enhanced protection. These findings may explain the observation that in humans with chronic malaria, activated effector memory cells are best maintained in conditions of repeated exposure.

Show MeSH
Related in: MedlinePlus