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Homeostatic proliferation and IL-7R alpha expression do not correlate with enhanced T cell proliferation and protection in chronic mouse malaria.

Stephens R, Seddon B, Langhorne J - PLoS ONE (2011)

Bottom Line: We have previously observed that chronic malaria infection enhances protection to re-infection, as well as enhancing B cell responses.Here, we show that chronic Plasmodium chabaudi malaria infection in mice enhances the expansion of CD4(+) T cells in a second infection, and that this correlates with increased expression of the IL-2/15 Receptor beta (CD122) on memory T cells, as well as increasing IL-2 producers on re-infection.Increased IL-7Rα (CD127) expression correlated, as previously reported with increased turnover of CD4 memory cells, however, this was not linked to protection or enhanced response to rechallenge, These data support the idea that antigen or IL-2 production resulting from chronic stimulation may play a role in an enhanced secondary T cell response.

View Article: PubMed Central - PubMed

Affiliation: Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom.

ABSTRACT
While chronic infection has been shown to enhance protection from disease caused by several pathogens, the mechanisms are not known. The gamma-c family of cytokines IL-7, IL-2, and IL-15 are implicated in homeostatic proliferation, which is thought to maintain T cell memory. However in chronic infection, prolonged antigen exposure itself may contribute to lymphocyte survival. We have previously observed that chronic malaria infection enhances protection to re-infection, as well as enhancing B cell responses. Here, we show that chronic Plasmodium chabaudi malaria infection in mice enhances the expansion of CD4(+) T cells in a second infection, and that this correlates with increased expression of the IL-2/15 Receptor beta (CD122) on memory T cells, as well as increasing IL-2 producers on re-infection. IL-2 has been recently linked to improved secondary proliferation, while the role of IL-7 in maintenance of CD4(+) memory cells has been demonstrated in homeostatic proliferation, but its role in protective memory populations in infectious disease protective has not been fully investigated. Increased IL-7Rα (CD127) expression correlated, as previously reported with increased turnover of CD4 memory cells, however, this was not linked to protection or enhanced response to rechallenge, These data support the idea that antigen or IL-2 production resulting from chronic stimulation may play a role in an enhanced secondary T cell response.

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Chronic infection increases IL-2+ memory cells and IL2/15Rβ+ memory fraction.Mice were infected with 105 P. chabaudi. On days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (−CQ). Two months after infection, A) mice were re-infected and intracellular cytokine staining performed on day 5 of reinfection. Isotype control is shown to the left. B) Splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and IL-2/15R beta (CD122). Naïve cells (CD44lo) were used as an internal control to set the quadrants (left). Data shown is the average of 4-5 mice per group and experiment was repeated twice with similar results. Contour plots (10% with outliers) are gated as described on each plot and are from representative animals. * indicates p≤0.05, ** p≤0.01.
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pone-0026686-g002: Chronic infection increases IL-2+ memory cells and IL2/15Rβ+ memory fraction.Mice were infected with 105 P. chabaudi. On days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (−CQ). Two months after infection, A) mice were re-infected and intracellular cytokine staining performed on day 5 of reinfection. Isotype control is shown to the left. B) Splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and IL-2/15R beta (CD122). Naïve cells (CD44lo) were used as an internal control to set the quadrants (left). Data shown is the average of 4-5 mice per group and experiment was repeated twice with similar results. Contour plots (10% with outliers) are gated as described on each plot and are from representative animals. * indicates p≤0.05, ** p≤0.01.

Mentions: IL-2 is a growth and survival factor for activated T cells, and promotes their proliferation [7], [14], [16]. It is induced by stimulation of the T cell receptor (TCR). In our experiments, spleens of mice with chronic P. chabaudi infection (-CQ) and hence exposed to continuing antigen, contained a greater proportion of IL-2-producing memory T cells (IL2+IFNγγ ~CD4+CD44hi) 5 days after re-infection (Figure 2A), compared with cells from infected mice treated with Chloroquine (+CQ), as measured by intracellular cytokine staining, which involves restimulation ex vivo. IL-2+IFNγ− is the largest population, and may help the other cells survive, while IFNγ+ cells are likely to be effector and effector memory cells. A significantly greater proportion of these memory cells also expressed the beta subunit of the IL-2 and IL-15 receptors, CD122, (IL-2/15Rβ) (Figure 2B), supporting the hypothesis that chronically stimulated CD4+ memory cells can maintain themselves by autocrine IL-2. There is also some evidence that CD4+ memory T cells depend on IL-15 [27], a family-member of IL-2. CD122 has also been shown to be expressed on CD8+ memory T cells that specifically do not depend on MHC or antigen for survival and can use IL-15 for survival in homeostasis [28].


Homeostatic proliferation and IL-7R alpha expression do not correlate with enhanced T cell proliferation and protection in chronic mouse malaria.

Stephens R, Seddon B, Langhorne J - PLoS ONE (2011)

Chronic infection increases IL-2+ memory cells and IL2/15Rβ+ memory fraction.Mice were infected with 105 P. chabaudi. On days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (−CQ). Two months after infection, A) mice were re-infected and intracellular cytokine staining performed on day 5 of reinfection. Isotype control is shown to the left. B) Splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and IL-2/15R beta (CD122). Naïve cells (CD44lo) were used as an internal control to set the quadrants (left). Data shown is the average of 4-5 mice per group and experiment was repeated twice with similar results. Contour plots (10% with outliers) are gated as described on each plot and are from representative animals. * indicates p≤0.05, ** p≤0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198788&req=5

pone-0026686-g002: Chronic infection increases IL-2+ memory cells and IL2/15Rβ+ memory fraction.Mice were infected with 105 P. chabaudi. On days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (−CQ). Two months after infection, A) mice were re-infected and intracellular cytokine staining performed on day 5 of reinfection. Isotype control is shown to the left. B) Splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and IL-2/15R beta (CD122). Naïve cells (CD44lo) were used as an internal control to set the quadrants (left). Data shown is the average of 4-5 mice per group and experiment was repeated twice with similar results. Contour plots (10% with outliers) are gated as described on each plot and are from representative animals. * indicates p≤0.05, ** p≤0.01.
Mentions: IL-2 is a growth and survival factor for activated T cells, and promotes their proliferation [7], [14], [16]. It is induced by stimulation of the T cell receptor (TCR). In our experiments, spleens of mice with chronic P. chabaudi infection (-CQ) and hence exposed to continuing antigen, contained a greater proportion of IL-2-producing memory T cells (IL2+IFNγγ ~CD4+CD44hi) 5 days after re-infection (Figure 2A), compared with cells from infected mice treated with Chloroquine (+CQ), as measured by intracellular cytokine staining, which involves restimulation ex vivo. IL-2+IFNγ− is the largest population, and may help the other cells survive, while IFNγ+ cells are likely to be effector and effector memory cells. A significantly greater proportion of these memory cells also expressed the beta subunit of the IL-2 and IL-15 receptors, CD122, (IL-2/15Rβ) (Figure 2B), supporting the hypothesis that chronically stimulated CD4+ memory cells can maintain themselves by autocrine IL-2. There is also some evidence that CD4+ memory T cells depend on IL-15 [27], a family-member of IL-2. CD122 has also been shown to be expressed on CD8+ memory T cells that specifically do not depend on MHC or antigen for survival and can use IL-15 for survival in homeostasis [28].

Bottom Line: We have previously observed that chronic malaria infection enhances protection to re-infection, as well as enhancing B cell responses.Here, we show that chronic Plasmodium chabaudi malaria infection in mice enhances the expansion of CD4(+) T cells in a second infection, and that this correlates with increased expression of the IL-2/15 Receptor beta (CD122) on memory T cells, as well as increasing IL-2 producers on re-infection.Increased IL-7Rα (CD127) expression correlated, as previously reported with increased turnover of CD4 memory cells, however, this was not linked to protection or enhanced response to rechallenge, These data support the idea that antigen or IL-2 production resulting from chronic stimulation may play a role in an enhanced secondary T cell response.

View Article: PubMed Central - PubMed

Affiliation: Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom.

ABSTRACT
While chronic infection has been shown to enhance protection from disease caused by several pathogens, the mechanisms are not known. The gamma-c family of cytokines IL-7, IL-2, and IL-15 are implicated in homeostatic proliferation, which is thought to maintain T cell memory. However in chronic infection, prolonged antigen exposure itself may contribute to lymphocyte survival. We have previously observed that chronic malaria infection enhances protection to re-infection, as well as enhancing B cell responses. Here, we show that chronic Plasmodium chabaudi malaria infection in mice enhances the expansion of CD4(+) T cells in a second infection, and that this correlates with increased expression of the IL-2/15 Receptor beta (CD122) on memory T cells, as well as increasing IL-2 producers on re-infection. IL-2 has been recently linked to improved secondary proliferation, while the role of IL-7 in maintenance of CD4(+) memory cells has been demonstrated in homeostatic proliferation, but its role in protective memory populations in infectious disease protective has not been fully investigated. Increased IL-7Rα (CD127) expression correlated, as previously reported with increased turnover of CD4 memory cells, however, this was not linked to protection or enhanced response to rechallenge, These data support the idea that antigen or IL-2 production resulting from chronic stimulation may play a role in an enhanced secondary T cell response.

Show MeSH
Related in: MedlinePlus