title: Age and CD161 expression contribute to inter-individual variation in interleukin-23 response in CD8+ memory human T cells.
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.
authors.affiliation: Department of Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
authors.forename: Judy H
authors.initials: JH
authors.lastname: Cho
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000276:immunology; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D053759:Interleukin-23 / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics* / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C515500:IL23R protein, human; D053759:Interleukin-23; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human