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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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Chronically stimulated memory T cells protect immunodeficient mice from parasitemia and pathology better than rested memory T cells.MSP1-specific CD4+ B5 memory (CD44hi) or naïve (CD44lowCD25−) T cells were purified from B5 TCR Tg mice infected 2.5 months previously and harbouring a chronic infection (−CQ, closed symbol/bar), or drug treated from days 30–34 to remove the chronic infection (+CQ, open symbol/bar). The cells (105) were transferred into RAG° recipients together with immune B cells (107) and the recipients infected with 5×104 P. chabaudi iRBC. A) Parasitemia (geometric mean +/−SEM) is at onset of patent parasitemia (day 6, left graph), and at peak parasitemia (days 8 and 10, middle graph) B) Peak weight change is shown as a measure of cachexia (left graph), maximum loss of body temperature (middle graph) and P.chabaudi -specific IgG antibodies (day 21) measured in the serum of the transferred RAG° animals by ELISA. C) Serum IL-10, IFN-γ, and TNFα were measured on day 7 in RAG° mice receiving Tg cells from chronically infected (closed symbols) or drug-treated mice (open symbols). The data shown are the means and SEM of 4–7 mice.
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ppat-1001208-g004: Chronically stimulated memory T cells protect immunodeficient mice from parasitemia and pathology better than rested memory T cells.MSP1-specific CD4+ B5 memory (CD44hi) or naïve (CD44lowCD25−) T cells were purified from B5 TCR Tg mice infected 2.5 months previously and harbouring a chronic infection (−CQ, closed symbol/bar), or drug treated from days 30–34 to remove the chronic infection (+CQ, open symbol/bar). The cells (105) were transferred into RAG° recipients together with immune B cells (107) and the recipients infected with 5×104 P. chabaudi iRBC. A) Parasitemia (geometric mean +/−SEM) is at onset of patent parasitemia (day 6, left graph), and at peak parasitemia (days 8 and 10, middle graph) B) Peak weight change is shown as a measure of cachexia (left graph), maximum loss of body temperature (middle graph) and P.chabaudi -specific IgG antibodies (day 21) measured in the serum of the transferred RAG° animals by ELISA. C) Serum IL-10, IFN-γ, and TNFα were measured on day 7 in RAG° mice receiving Tg cells from chronically infected (closed symbols) or drug-treated mice (open symbols). The data shown are the means and SEM of 4–7 mice.

Mentions: After adoptive transfer of chronically simulated or rested CD4 T cells into recipient mice, there were two clear major measurable effects of these cell transfers on parasitemia (Figure 4A); a delay in appearance of early parasitemia, and a reduction in peak parasitemia. Mice receiving chronically stimulated memory T cells (−CQ) showed a delayed onset of parasitemia (Figure 4A, left graph), showing that these cells were more effective in controlling early parasite growth. Consistent with this, chronically stimulated memory T cells also reduced peak parasitemia (p = 0.02) compared with resting cells, (Figure 4A, right graph) or naïve cells (data not shown). Consistent with reduced parasitemia, mice receiving chronically stimulated cells exhibited less pathology than mice receiving rested memory T cells (Figure 4B) and naïve cells (not shown). Thus chronically stimulated malaria-specific memory T cells show an enhanced early protective effect with reduced parasitemias and reduced pathology compared with rested memory T cells. Furthermore, chronically stimulated B5 memory T cells provided more effective help for a P. chabaudi-specific antibody response than resting memory B5 cells (Figure 4B). RAG° mice receiving chronically stimulated T cells also had higher levels of TNFα, IFN-γ and IL-10, in plasma at day 7 of infection (Figure 4C), than those receiving rested T cells. These inflammatory cytokines may enhance parasite killing, while IL-10, may regulate their pathogenic effects, as has been described previously [35].


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

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

Chronically stimulated memory T cells protect immunodeficient mice from parasitemia and pathology better than rested memory T cells.MSP1-specific CD4+ B5 memory (CD44hi) or naïve (CD44lowCD25−) T cells were purified from B5 TCR Tg mice infected 2.5 months previously and harbouring a chronic infection (−CQ, closed symbol/bar), or drug treated from days 30–34 to remove the chronic infection (+CQ, open symbol/bar). The cells (105) were transferred into RAG° recipients together with immune B cells (107) and the recipients infected with 5×104 P. chabaudi iRBC. A) Parasitemia (geometric mean +/−SEM) is at onset of patent parasitemia (day 6, left graph), and at peak parasitemia (days 8 and 10, middle graph) B) Peak weight change is shown as a measure of cachexia (left graph), maximum loss of body temperature (middle graph) and P.chabaudi -specific IgG antibodies (day 21) measured in the serum of the transferred RAG° animals by ELISA. C) Serum IL-10, IFN-γ, and TNFα were measured on day 7 in RAG° mice receiving Tg cells from chronically infected (closed symbols) or drug-treated mice (open symbols). The data shown are the means and SEM of 4–7 mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991260&req=5

ppat-1001208-g004: Chronically stimulated memory T cells protect immunodeficient mice from parasitemia and pathology better than rested memory T cells.MSP1-specific CD4+ B5 memory (CD44hi) or naïve (CD44lowCD25−) T cells were purified from B5 TCR Tg mice infected 2.5 months previously and harbouring a chronic infection (−CQ, closed symbol/bar), or drug treated from days 30–34 to remove the chronic infection (+CQ, open symbol/bar). The cells (105) were transferred into RAG° recipients together with immune B cells (107) and the recipients infected with 5×104 P. chabaudi iRBC. A) Parasitemia (geometric mean +/−SEM) is at onset of patent parasitemia (day 6, left graph), and at peak parasitemia (days 8 and 10, middle graph) B) Peak weight change is shown as a measure of cachexia (left graph), maximum loss of body temperature (middle graph) and P.chabaudi -specific IgG antibodies (day 21) measured in the serum of the transferred RAG° animals by ELISA. C) Serum IL-10, IFN-γ, and TNFα were measured on day 7 in RAG° mice receiving Tg cells from chronically infected (closed symbols) or drug-treated mice (open symbols). The data shown are the means and SEM of 4–7 mice.
Mentions: After adoptive transfer of chronically simulated or rested CD4 T cells into recipient mice, there were two clear major measurable effects of these cell transfers on parasitemia (Figure 4A); a delay in appearance of early parasitemia, and a reduction in peak parasitemia. Mice receiving chronically stimulated memory T cells (−CQ) showed a delayed onset of parasitemia (Figure 4A, left graph), showing that these cells were more effective in controlling early parasite growth. Consistent with this, chronically stimulated memory T cells also reduced peak parasitemia (p = 0.02) compared with resting cells, (Figure 4A, right graph) or naïve cells (data not shown). Consistent with reduced parasitemia, mice receiving chronically stimulated cells exhibited less pathology than mice receiving rested memory T cells (Figure 4B) and naïve cells (not shown). Thus chronically stimulated malaria-specific memory T cells show an enhanced early protective effect with reduced parasitemias and reduced pathology compared with rested memory T cells. Furthermore, chronically stimulated B5 memory T cells provided more effective help for a P. chabaudi-specific antibody response than resting memory B5 cells (Figure 4B). RAG° mice receiving chronically stimulated T cells also had higher levels of TNFα, IFN-γ and IL-10, in plasma at day 7 of infection (Figure 4C), than those receiving rested T cells. These inflammatory cytokines may enhance parasite killing, while IL-10, may regulate their pathogenic effects, as has been described previously [35].

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