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Premature CD4+ T cell aging and its contribution to lymphopenia-induced proliferation of memory cells in autoimmune-prone non-obese diabetic mice.

Sheu TT, Chiang BL, Yen JH, Lin WC - PLoS ONE (2014)

Bottom Line: This was accompanied by an increase in the percentage of memory cells, leading to a reduced naïve/memory ratio.This process preferentially contributed to LIP of memory cells.Given that CD28 and IL-2 play important roles in Treg function, the relationships between premature CD4(+) T cell aging and lymphopenia as well as Treg defects in autoimmune-prone NOD mice are proposed.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Tzu Chi University, Hualien, Taiwan, Republic of China ; Institute of Microbiology, Immunology and Biochemistry, Tzu Chi University, Hualien, Taiwan, Republic of China.

ABSTRACT
Lymphopenia-induced proliferation (LIP), a mechanism to maintain a constant number of T cells in circulation, occurs in both normal aging and autoimmune disease. The incidence of most autoimmune diseases increases with age, and premature CD4(+) T cell aging has been reported in several autoimmune diseases. In this study, we tested the hypothesis that premature CD4(+) T cell aging can cause autoimmune disease by examining whether premature CD4(+) T cell aging exists and causes LIP in our mouse model. Non-obese diabetic (NOD) mice were used because, in addition to Treg defects, the LIP of T cells has been shown to plays a causative role in the development of insulin-dependent diabetes mellitus (IDDM) in these mice. We found that with advancing age, NOD mice exhibited an accelerated decrease in the number of CD4(+) T cells due to the loss of naïve cells. This was accompanied by an increase in the percentage of memory cells, leading to a reduced naïve/memory ratio. In addition, both the percentage of CD28(+) cells in CD4(+) T cells and IL-2 production decreased, while the percentage of FAS(+)CD44(+) increased, suggesting that NOD mice exhibit premature CD4(+) T cell aging. This process preferentially contributed to LIP of memory cells. Therefore, our results suggest that premature CD4(+) T cell aging underlies the development of IDDM in NOD mice. Given that CD28 and IL-2 play important roles in Treg function, the relationships between premature CD4(+) T cell aging and lymphopenia as well as Treg defects in autoimmune-prone NOD mice are proposed.

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Reduced IL-2 production from splenocytes of NOD mice compared to age-matched Balb/c mice.The bar plots show the IL-2 level in each age group. Data are shown as mean ± SEM (Balb/c: n = 8−10 mice per group; NOD: n = 8−10 mice per group). Splenocytes isolated from Balb/c and NOD mice were stimulated with Con A and culture supernatants were harvested to determine IL-2 levels. *The values for NOD mice were significantly different from the values for Balb/c mice at P<0.05.
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pone-0089379-g004: Reduced IL-2 production from splenocytes of NOD mice compared to age-matched Balb/c mice.The bar plots show the IL-2 level in each age group. Data are shown as mean ± SEM (Balb/c: n = 8−10 mice per group; NOD: n = 8−10 mice per group). Splenocytes isolated from Balb/c and NOD mice were stimulated with Con A and culture supernatants were harvested to determine IL-2 levels. *The values for NOD mice were significantly different from the values for Balb/c mice at P<0.05.

Mentions: IL-2 is an important cytokine for T cell proliferation and is mainly produced by activated CD4+ T cells. Reduced production of IL-2 from CD4+ T cells is evident in older humans and mice, thus providing a marker of T cell aging. IL-2 can mediate biological responses through binding to its high-affinity receptor and this IL-2/IL-2R interaction also leads to endocytosis of this complex to limit IL-2 signal transduction [48]. Therefore, the IL-2 level in culture medium is the net result of both secreting and internalization pathways. To examine IL-2 production with culture medium, a time point when highest IL-2 level reached should be chosen. To further explore the CD4+ T cell aging phenomenon in NOD mice, we stimulated splenocytes with Con A for 20 hours and examined IL-2 levels in culture supernatants. We chose 20 hour post-stimulation since it has been shown that IL-2 level in culture medium reaches and maintains on a maximum level between 18 hours and 48 hours post Con A stimulation of splenocytes isolated from young C57BL/6 mice [49]. As shown in Figure 4, in general, the IL-2 production in splenocytes isolated from NOD mice is less than that isolated from control Balb/c mice. The difference between control and NOD mice is significant in age groups I, II and III but not in age groups IV (Figure 4). Interestingly, in age groups I and III the percentage of naïve CD4+ T cells is the same in both control and NOD mice, while the reduced IL-2 production in NOD mice suggests that the presence of intrinsic defects may exist in the naïve cells of NOD mice. It has been shown that recent thymic emigrants generated from aged mice possess intrinsic defects and produce less IL-2 [22]. This result suggests that, by comparison with control Balb/c mice, NOD mice undergo a dynamic premature T cell aging process with the presence of intrinsic defects in the naïve cells.


Premature CD4+ T cell aging and its contribution to lymphopenia-induced proliferation of memory cells in autoimmune-prone non-obese diabetic mice.

Sheu TT, Chiang BL, Yen JH, Lin WC - PLoS ONE (2014)

Reduced IL-2 production from splenocytes of NOD mice compared to age-matched Balb/c mice.The bar plots show the IL-2 level in each age group. Data are shown as mean ± SEM (Balb/c: n = 8−10 mice per group; NOD: n = 8−10 mice per group). Splenocytes isolated from Balb/c and NOD mice were stimulated with Con A and culture supernatants were harvested to determine IL-2 levels. *The values for NOD mice were significantly different from the values for Balb/c mice at P<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3935863&req=5

pone-0089379-g004: Reduced IL-2 production from splenocytes of NOD mice compared to age-matched Balb/c mice.The bar plots show the IL-2 level in each age group. Data are shown as mean ± SEM (Balb/c: n = 8−10 mice per group; NOD: n = 8−10 mice per group). Splenocytes isolated from Balb/c and NOD mice were stimulated with Con A and culture supernatants were harvested to determine IL-2 levels. *The values for NOD mice were significantly different from the values for Balb/c mice at P<0.05.
Mentions: IL-2 is an important cytokine for T cell proliferation and is mainly produced by activated CD4+ T cells. Reduced production of IL-2 from CD4+ T cells is evident in older humans and mice, thus providing a marker of T cell aging. IL-2 can mediate biological responses through binding to its high-affinity receptor and this IL-2/IL-2R interaction also leads to endocytosis of this complex to limit IL-2 signal transduction [48]. Therefore, the IL-2 level in culture medium is the net result of both secreting and internalization pathways. To examine IL-2 production with culture medium, a time point when highest IL-2 level reached should be chosen. To further explore the CD4+ T cell aging phenomenon in NOD mice, we stimulated splenocytes with Con A for 20 hours and examined IL-2 levels in culture supernatants. We chose 20 hour post-stimulation since it has been shown that IL-2 level in culture medium reaches and maintains on a maximum level between 18 hours and 48 hours post Con A stimulation of splenocytes isolated from young C57BL/6 mice [49]. As shown in Figure 4, in general, the IL-2 production in splenocytes isolated from NOD mice is less than that isolated from control Balb/c mice. The difference between control and NOD mice is significant in age groups I, II and III but not in age groups IV (Figure 4). Interestingly, in age groups I and III the percentage of naïve CD4+ T cells is the same in both control and NOD mice, while the reduced IL-2 production in NOD mice suggests that the presence of intrinsic defects may exist in the naïve cells of NOD mice. It has been shown that recent thymic emigrants generated from aged mice possess intrinsic defects and produce less IL-2 [22]. This result suggests that, by comparison with control Balb/c mice, NOD mice undergo a dynamic premature T cell aging process with the presence of intrinsic defects in the naïve cells.

Bottom Line: This was accompanied by an increase in the percentage of memory cells, leading to a reduced naïve/memory ratio.This process preferentially contributed to LIP of memory cells.Given that CD28 and IL-2 play important roles in Treg function, the relationships between premature CD4(+) T cell aging and lymphopenia as well as Treg defects in autoimmune-prone NOD mice are proposed.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Tzu Chi University, Hualien, Taiwan, Republic of China ; Institute of Microbiology, Immunology and Biochemistry, Tzu Chi University, Hualien, Taiwan, Republic of China.

ABSTRACT
Lymphopenia-induced proliferation (LIP), a mechanism to maintain a constant number of T cells in circulation, occurs in both normal aging and autoimmune disease. The incidence of most autoimmune diseases increases with age, and premature CD4(+) T cell aging has been reported in several autoimmune diseases. In this study, we tested the hypothesis that premature CD4(+) T cell aging can cause autoimmune disease by examining whether premature CD4(+) T cell aging exists and causes LIP in our mouse model. Non-obese diabetic (NOD) mice were used because, in addition to Treg defects, the LIP of T cells has been shown to plays a causative role in the development of insulin-dependent diabetes mellitus (IDDM) in these mice. We found that with advancing age, NOD mice exhibited an accelerated decrease in the number of CD4(+) T cells due to the loss of naïve cells. This was accompanied by an increase in the percentage of memory cells, leading to a reduced naïve/memory ratio. In addition, both the percentage of CD28(+) cells in CD4(+) T cells and IL-2 production decreased, while the percentage of FAS(+)CD44(+) increased, suggesting that NOD mice exhibit premature CD4(+) T cell aging. This process preferentially contributed to LIP of memory cells. Therefore, our results suggest that premature CD4(+) T cell aging underlies the development of IDDM in NOD mice. Given that CD28 and IL-2 play important roles in Treg function, the relationships between premature CD4(+) T cell aging and lymphopenia as well as Treg defects in autoimmune-prone NOD mice are proposed.

Show MeSH
Related in: MedlinePlus