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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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IL-23 responsiveness in CD8+CD45RO+ memory T cells is correlated with IL-23R, RORC and CD161 mRNA expression.Quantitative RT-PCR assays were performed in FACS-sorted CD8+CD45RO+ memory T cells from 15 individuals selected for having a range of IL-23 responsiveness, which were measured by whole blood phospho-flow assays for IL-23-mediated pSTAT3 induction (log2). Correlations were assessed between IL-23 responsiveness and (A) IL-23R, (B) RORC, (C) CD161, (D) RORA, and (E) STAT3 mRNA expression.
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pone-0057746-g004: IL-23 responsiveness in CD8+CD45RO+ memory T cells is correlated with IL-23R, RORC and CD161 mRNA expression.Quantitative RT-PCR assays were performed in FACS-sorted CD8+CD45RO+ memory T cells from 15 individuals selected for having a range of IL-23 responsiveness, which were measured by whole blood phospho-flow assays for IL-23-mediated pSTAT3 induction (log2). Correlations were assessed between IL-23 responsiveness and (A) IL-23R, (B) RORC, (C) CD161, (D) RORA, and (E) STAT3 mRNA expression.

Mentions: We also examined the microarray data for differential expression of select genes of known relevance to the IL-23 pathway (Table 1 and Table S2). Compared to IL-23-non-responsive individuals, we observed increased mRNA expressions of IL-23R, RORC (RORγt, RAR-related orphan receptor C), and RORA (RAR-related orphan receptor A) as well as reduced expression of TBX21 (T-box 21, also known as T-bet) in IL-23-responsive subjects (Table 1). No differential expression was detected for other members of the IL-23 pathway (e.g., IL12RB1, JAK2, TYK2, STAT3, CCR6 or IL17), nor for other Tc1-associated genes (e.g., IFNG, perforin, or granzyme B), between the IL-23-non-responsive and the responsive subjects (Table 1 and Table S2). To further evaluate the correlation between expression levels of these IL-23 pathway genes and IL-23 responsiveness, we performed real-time RT-PCR assays for selected genes in CD8+CD45RO+ memory T cells sorted from 15 individuals that had been selected for having a range of different IL-23 responsiveness. Significant positive correlations were observed between IL-23 responsiveness and mRNA levels for IL-23R (Figure 4A, r = 0.82, p<0.001), RORC (Figure 4B, r = 0.72, p = 0.002) and CD161 (Fig. 4C, r = 0.75, p = 0.002). In contrast, we did not observe a significant correlation in IL-23 response with RORA or STAT3 mRNA expressions (Figure 4D–4E). Therefore, CD8+CD45RO+ memory T cells with increasing IL-23 responsiveness demonstrate increasing levels of CD161, IL-23R, and RORC mRNA expression.


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)

IL-23 responsiveness in CD8+CD45RO+ memory T cells is correlated with IL-23R, RORC and CD161 mRNA expression.Quantitative RT-PCR assays were performed in FACS-sorted CD8+CD45RO+ memory T cells from 15 individuals selected for having a range of IL-23 responsiveness, which were measured by whole blood phospho-flow assays for IL-23-mediated pSTAT3 induction (log2). Correlations were assessed between IL-23 responsiveness and (A) IL-23R, (B) RORC, (C) CD161, (D) RORA, and (E) STAT3 mRNA expression.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585933&req=5

pone-0057746-g004: IL-23 responsiveness in CD8+CD45RO+ memory T cells is correlated with IL-23R, RORC and CD161 mRNA expression.Quantitative RT-PCR assays were performed in FACS-sorted CD8+CD45RO+ memory T cells from 15 individuals selected for having a range of IL-23 responsiveness, which were measured by whole blood phospho-flow assays for IL-23-mediated pSTAT3 induction (log2). Correlations were assessed between IL-23 responsiveness and (A) IL-23R, (B) RORC, (C) CD161, (D) RORA, and (E) STAT3 mRNA expression.
Mentions: We also examined the microarray data for differential expression of select genes of known relevance to the IL-23 pathway (Table 1 and Table S2). Compared to IL-23-non-responsive individuals, we observed increased mRNA expressions of IL-23R, RORC (RORγt, RAR-related orphan receptor C), and RORA (RAR-related orphan receptor A) as well as reduced expression of TBX21 (T-box 21, also known as T-bet) in IL-23-responsive subjects (Table 1). No differential expression was detected for other members of the IL-23 pathway (e.g., IL12RB1, JAK2, TYK2, STAT3, CCR6 or IL17), nor for other Tc1-associated genes (e.g., IFNG, perforin, or granzyme B), between the IL-23-non-responsive and the responsive subjects (Table 1 and Table S2). To further evaluate the correlation between expression levels of these IL-23 pathway genes and IL-23 responsiveness, we performed real-time RT-PCR assays for selected genes in CD8+CD45RO+ memory T cells sorted from 15 individuals that had been selected for having a range of different IL-23 responsiveness. Significant positive correlations were observed between IL-23 responsiveness and mRNA levels for IL-23R (Figure 4A, r = 0.82, p<0.001), RORC (Figure 4B, r = 0.72, p = 0.002) and CD161 (Fig. 4C, r = 0.75, p = 0.002). In contrast, we did not observe a significant correlation in IL-23 response with RORA or STAT3 mRNA expressions (Figure 4D–4E). Therefore, CD8+CD45RO+ memory T cells with increasing IL-23 responsiveness demonstrate increasing levels of CD161, IL-23R, and RORC mRNA expression.

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