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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 reduces IL-7Rαhi memory cells in both memory subsets.Mice were infected with 105 P. chabaudi. Days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (-CQ). 2.5 months after infection, splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and (A, B) IL-7Rα (CD127) or incorporation of BrdU dosed into the water days 62–72 as an indicator of homeostatic proliferation, (C, D). Naïve cells (CD44lo) were used as an internal control to set the quadrants (B, left). Dotted lines represent chloroquine treated mice (+CQ) while bold lines represent chronic infection (-CQ). 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-g003: Chronic infection reduces IL-7Rαhi memory cells in both memory subsets.Mice were infected with 105 P. chabaudi. Days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (-CQ). 2.5 months after infection, splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and (A, B) IL-7Rα (CD127) or incorporation of BrdU dosed into the water days 62–72 as an indicator of homeostatic proliferation, (C, D). Naïve cells (CD44lo) were used as an internal control to set the quadrants (B, left). Dotted lines represent chloroquine treated mice (+CQ) while bold lines represent chronic infection (-CQ). 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-7 has been shown to promote survival of both naïve and memory CD4+ T cells and IL-7Rα has been shown in several studies to be up-regulated on antigen-independent memory T cells generated in acute infection [28], [29]. In order to investigate the use of this cytokine by CD4+ memory T cells in chronic infection, we measured the proportion of IL-7Rα (CD127)hi CD4+ memory cells in this P. chabaudi infection. Naïve (CD44lo) splenic CD4+ T cells were IL-7Rαlo [10] (Figure 3, left contour plot), allowing us to set the gate for this cytokine receptor, which has a slightly higher expression level on memory T cells (Tcm: CD44hi, CD62Lhi; Tem: CD44hiCD62Llo, Figure 3, middle and right contour plots). In order to measure proliferation of T cells in the memory phase, BrdU was administered in the drinking water from days 62–72 post-infection. Interestingly, proliferation in this period was decreased in animals with chronic infection. This suggests that although they are better protected from re-infection [22], T cells do not have increased homeostatic proliferation.


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 reduces IL-7Rαhi memory cells in both memory subsets.Mice were infected with 105 P. chabaudi. Days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (-CQ). 2.5 months after infection, splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and (A, B) IL-7Rα (CD127) or incorporation of BrdU dosed into the water days 62–72 as an indicator of homeostatic proliferation, (C, D). Naïve cells (CD44lo) were used as an internal control to set the quadrants (B, left). Dotted lines represent chloroquine treated mice (+CQ) while bold lines represent chronic infection (-CQ). 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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198788&req=5

pone-0026686-g003: Chronic infection reduces IL-7Rαhi memory cells in both memory subsets.Mice were infected with 105 P. chabaudi. Days 30–34 half of the mice were treated with chloroquine (+CQ), while the other mice retained a chronic infection (-CQ). 2.5 months after infection, splenocytes were analyzed by flow cytometry for CD4, CD44, CD62L and (A, B) IL-7Rα (CD127) or incorporation of BrdU dosed into the water days 62–72 as an indicator of homeostatic proliferation, (C, D). Naïve cells (CD44lo) were used as an internal control to set the quadrants (B, left). Dotted lines represent chloroquine treated mice (+CQ) while bold lines represent chronic infection (-CQ). 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-7 has been shown to promote survival of both naïve and memory CD4+ T cells and IL-7Rα has been shown in several studies to be up-regulated on antigen-independent memory T cells generated in acute infection [28], [29]. In order to investigate the use of this cytokine by CD4+ memory T cells in chronic infection, we measured the proportion of IL-7Rα (CD127)hi CD4+ memory cells in this P. chabaudi infection. Naïve (CD44lo) splenic CD4+ T cells were IL-7Rαlo [10] (Figure 3, left contour plot), allowing us to set the gate for this cytokine receptor, which has a slightly higher expression level on memory T cells (Tcm: CD44hi, CD62Lhi; Tem: CD44hiCD62Llo, Figure 3, middle and right contour plots). In order to measure proliferation of T cells in the memory phase, BrdU was administered in the drinking water from days 62–72 post-infection. Interestingly, proliferation in this period was decreased in animals with chronic infection. This suggests that although they are better protected from re-infection [22], T cells do not have increased homeostatic proliferation.

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