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Age and CD161 expression contribute to inter-individual variation in interleukin-23 response in CD8+ memory human T cells.

Shen H, Zhang W, Abraham C, Cho JH - PLoS ONE (2013)

Bottom Line: Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = -0.34, p = 0.05).Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population.Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.

ABSTRACT
The interleukin-23 (IL-23) pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation) in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant (Pearson's correlation coefficient, r = -0.37, p = 0.001) source of variability observed in CD8+CD45RO+ memory T cells, with IL-23 responsiveness gradually decreasing with increasing age. Relative to cells from individuals demonstrating low responsiveness to IL-23 stimulation, CD8+CD45RO+ memory T cells from individuals demonstrating high responsiveness to IL-23 stimulation showed increased gene expression for IL-23 receptor (IL-23R), RORC (RORγt) and CD161 (KLRB1), whereas RORA (RORα) and STAT3 expression were equivalent. Similar to CD4+ memory T cells, IL-23 responsiveness is confined to the CD161+ subset in CD8+CD45RO+ memory T cells, suggesting a similar CD161+ precursor as has been reported for CD4+ Th17 cells. We observed a very strong positive correlation between IL-23 responsiveness and the fraction of CD161+, CD8+CD45RO+ memory T cells (r = 0.80, p<0.001). Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = -0.34, p = 0.05). Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population. Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes.

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Age-related correlation and subset analysis for IL-23-mediated pSTAT3 induction in CD8+CD45RO+ memory T cells and CD3+CD56+ NKT cells.Peripheral whole blood was stimulated with 100 ng/ml IL-23 for 15 minutes and pSTAT3 induction was assessed by phospho-flow assay. IL-23 responsiveness was calculated as the log2 ratio of GMFI of pSTAT3 in stimulated vs. unstimulated samples. Age is significantly associated with IL-23 responsiveness in (A) CD8+CD45RO+ memory T cells (n = 82, r = −0.37, p = 0.001), but not in (B) CD3+CD56+ NKT cells (n = 82, p = 0.50). (C) IL-23 responsive NKT cells are confined to the CD4−CD8+ and CD4−CD8− subsets (n = 20).
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pone-0057746-g003: Age-related correlation and subset analysis for IL-23-mediated pSTAT3 induction in CD8+CD45RO+ memory T cells and CD3+CD56+ NKT cells.Peripheral whole blood was stimulated with 100 ng/ml IL-23 for 15 minutes and pSTAT3 induction was assessed by phospho-flow assay. IL-23 responsiveness was calculated as the log2 ratio of GMFI of pSTAT3 in stimulated vs. unstimulated samples. Age is significantly associated with IL-23 responsiveness in (A) CD8+CD45RO+ memory T cells (n = 82, r = −0.37, p = 0.001), but not in (B) CD3+CD56+ NKT cells (n = 82, p = 0.50). (C) IL-23 responsive NKT cells are confined to the CD4−CD8+ and CD4−CD8− subsets (n = 20).

Mentions: We next considered factors that might contribute to the significant inter-individual variability in IL-23 responsiveness observed in primary human cells. As it is known that gender and aging may contribute to inter-individual variability in human immune responses [17]–[20], we evaluated gender and age as potential factors contributing to inter-individual variability in IL-23 responsiveness in 82 randomly selected healthy individuals. There was no significant difference in IL-23 responsiveness between males (n = 24) and females (n = 58) (t-test, p = 0.18 and 0.38 in CD8+CD45RO+ memory T cells and CD3+CD56+ NKT cells, respectively, data not shown). However, in CD8+CD45RO+ memory T cells, we observed a modest but significant correlation of decreased IL-23 responsiveness with increasing age (Pearson’s correlation coefficient r = −0.37, p = 0.001, Figure 3A).


Age and CD161 expression contribute to inter-individual variation in interleukin-23 response in CD8+ memory human T cells.

Shen H, Zhang W, Abraham C, Cho JH - PLoS ONE (2013)

Age-related correlation and subset analysis for IL-23-mediated pSTAT3 induction in CD8+CD45RO+ memory T cells and CD3+CD56+ NKT cells.Peripheral whole blood was stimulated with 100 ng/ml IL-23 for 15 minutes and pSTAT3 induction was assessed by phospho-flow assay. IL-23 responsiveness was calculated as the log2 ratio of GMFI of pSTAT3 in stimulated vs. unstimulated samples. Age is significantly associated with IL-23 responsiveness in (A) CD8+CD45RO+ memory T cells (n = 82, r = −0.37, p = 0.001), but not in (B) CD3+CD56+ NKT cells (n = 82, p = 0.50). (C) IL-23 responsive NKT cells are confined to the CD4−CD8+ and CD4−CD8− subsets (n = 20).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585933&req=5

pone-0057746-g003: Age-related correlation and subset analysis for IL-23-mediated pSTAT3 induction in CD8+CD45RO+ memory T cells and CD3+CD56+ NKT cells.Peripheral whole blood was stimulated with 100 ng/ml IL-23 for 15 minutes and pSTAT3 induction was assessed by phospho-flow assay. IL-23 responsiveness was calculated as the log2 ratio of GMFI of pSTAT3 in stimulated vs. unstimulated samples. Age is significantly associated with IL-23 responsiveness in (A) CD8+CD45RO+ memory T cells (n = 82, r = −0.37, p = 0.001), but not in (B) CD3+CD56+ NKT cells (n = 82, p = 0.50). (C) IL-23 responsive NKT cells are confined to the CD4−CD8+ and CD4−CD8− subsets (n = 20).
Mentions: We next considered factors that might contribute to the significant inter-individual variability in IL-23 responsiveness observed in primary human cells. As it is known that gender and aging may contribute to inter-individual variability in human immune responses [17]–[20], we evaluated gender and age as potential factors contributing to inter-individual variability in IL-23 responsiveness in 82 randomly selected healthy individuals. There was no significant difference in IL-23 responsiveness between males (n = 24) and females (n = 58) (t-test, p = 0.18 and 0.38 in CD8+CD45RO+ memory T cells and CD3+CD56+ NKT cells, respectively, data not shown). However, in CD8+CD45RO+ memory T cells, we observed a modest but significant correlation of decreased IL-23 responsiveness with increasing age (Pearson’s correlation coefficient r = −0.37, p = 0.001, Figure 3A).

Bottom Line: Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = -0.34, p = 0.05).Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population.Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.

ABSTRACT
The interleukin-23 (IL-23) pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation) in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant (Pearson's correlation coefficient, r = -0.37, p = 0.001) source of variability observed in CD8+CD45RO+ memory T cells, with IL-23 responsiveness gradually decreasing with increasing age. Relative to cells from individuals demonstrating low responsiveness to IL-23 stimulation, CD8+CD45RO+ memory T cells from individuals demonstrating high responsiveness to IL-23 stimulation showed increased gene expression for IL-23 receptor (IL-23R), RORC (RORγt) and CD161 (KLRB1), whereas RORA (RORα) and STAT3 expression were equivalent. Similar to CD4+ memory T cells, IL-23 responsiveness is confined to the CD161+ subset in CD8+CD45RO+ memory T cells, suggesting a similar CD161+ precursor as has been reported for CD4+ Th17 cells. We observed a very strong positive correlation between IL-23 responsiveness and the fraction of CD161+, CD8+CD45RO+ memory T cells (r = 0.80, p<0.001). Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = -0.34, p = 0.05). Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population. Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes.

Show MeSH
Related in: MedlinePlus