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Effector Memory T Cells + Regulation of IL-17 in Human CCR6

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Effector Memory T Cells + Regulation of IL-17 in Human CCR6 Regulation of IL-17 in Human CCR6+ Effector Memory T Cells Hong Liu and Christine Rohowsky-Kochan This information is current as J Immunol 2008; 180:7948-7957; ; of September 24, 2021. doi: 10.4049/jimmunol.180.12.7948 http://www.jimmunol.org/content/180/12/7948 Downloaded from References This article cites 25 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/180/12/7948.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Regulation of IL-17 in Human CCR6؉ Effector Memory T Cells1 Hong Liu and Christine Rohowsky-Kochan2 IL-17–secreting T cells represent a distinct CD4؉ effector T cell lineage (Th17) that appears to be essential in the pathogenesis of numerous inflammatory and autoimmune diseases. Although extensively studied in the murine system, human Th17 cells have not been well characterized. In this study, we identify CD4؉CD45RO؉CCR7؊CCR6؉ effector memory T cells as the principal IL-17-secreting T cells. Human Th17 cells have a unique cytokine profile because the majority coexpress TNF-␣ but not IL-6 and a minor subset express IL-17 with IL-22 or IL-17 and IFN-␥. We demonstrate that the cytokines that promote the differentiation of human naive T cells into IL-17-secreting cells regulate IL-17 production by memory T cells. IL-1␤ alone or in association with IL-23 and IL-6 markedly increase IL-17؉ CCR6؉ memory T cells and induce IL-17 production in CCR6؊ memory T cells. We ؉ also show that T cell activation induces Foxp3 expression in T cells and that the balance between the percentage of Foxp3 and Downloaded from IL-17؉ T cells is inversely influenced by the cytokine environment. These studies suggest that the cytokine environment may play a critical role in the expansion of memory T cells in chronic autoimmune diseases. The Journal of Immunology, 2008, 180: 7948–7957. nterleukin-17 or IL-17A is the founding member of a family that for human naive CD4ϩ T cells, expression of the transcription ␥ ␤ of cytokines, comprising six members IL-17A-IL-17F. IL-17 factor ROR t and Th17 polarization were induced by IL-1 and http://www.jimmunol.org/ I is a proinflammatory cytokine that induces the production of IL-6 and suppressed by TGF-␤ and IL-12, whereas another group various inflammatory mediators including IL-6, IL-8, GM-CSF, showed that IL-1␤ and IL-23 were critical in the development of and PGE2 from fibroblasts, epithelial, and endothelial cells. IL-17 human Th17 cells (9, 10). Very little work has been done on the has been implicated in mediating protection against extracellular characterization of the IL-17-secreting memory T cells and the microbes and in playing a critical role in the pathogenesis of sev- factors that regulate IL-17 production. Initially IL-17 mRNA ex- eral inflammatory and autoimmune disorders. In both experimental pression was reported to be restricted to CD4ϩCD45ROϩ T cells autoimmune encephalomyelitis and type II collagen-induced ar- (11), although no protein data were shown. IL-17 expression in thritis, the animal models for multiple sclerosis and rheumatoid CD8ϩ memory T cells was shown to require costimulatory sig- ϩ ϩ arthritis, respectively, it was shown that IL-17-secreting CD4 nals from accessory cells because polyclonal activation of CD8 by guest on September 24, 2021 effector T cells are highly pathogenic and essential for the estab- CD45ROϩ T cells alone did not result in IL-17 production (12). lishment of organ-specific autoimmunity (1, 2). Recently, IL-17-secreting T cells were detected in both The IL-17-secreting Th cells (Th17 cells) have been described CD4ϩCD45ROϩCCR7ϩ central memory and CD4ϩCD45ROϩ in mice as a distinct subset of effector cells whose differentiation CCR7Ϫ effector memory T cell subsets, with central memory from naive T cells are promoted by IL-6 and TGF-␤ and require T cells having a 3-fold higher number than effector memory T the transcription factor ROR␥t (3–6). IFN-␥ and IL-4 inhibit the cells (13). Further analysis showed that the IL-17ϩ T cells ex- differentiation of naive T cells into Th17 cells, whereas IL-23 is pressed both CCR6 and CCR4 chemokine receptors. Moreover, necessary for the expansion and survival of IL-17-secreting mem- a number of studies have not been able to detect IL-17-produc- ory T cells (7, 8). In experimental autoimmune encephalomyelitis, ing T cells in the peripheral blood of healthy individuals only in IL-23 was found to be essential in the expansion of pathogenic, patients with inflammatory conditions (14, 15). The cellular autoreactive CD4ϩ T cells, which secreted IL-17A, IL-17F, IL-6, phenotype and regulation of human memory T cells secreting and TNF-␣ (1). IL-17 has not fully been elucidated. Since the identification of murine Th17 cells, extensive efforts In this study, we demonstrate that effector memory T cells that have been made to characterize the differentiation of naive CD4ϩ express the chemokine receptor CCR6 are the principal IL-17- IL-17-secreting T cells in humans. Recently, one group reported secreting cells and that IL-1␤ markedly enhances IL-17 production by increasing the percentage of CCR6ϩ IL-17ϩ T cells and by inducing IL-17 production in CCR6Ϫ memory T cells. Human Department of Neurology and Neurosciences, University of Medicine and Dentistry Th17 cells have a unique cytokine profile as the majority coexpress New Jersey-New Jersey Medical School, Newark, NJ 07103 TNF-␣ but not IL-6 and a minor subset expresses IL-17 with IL-22 Received for publication April 3, 2008. Accepted for publication April 3, 2008. or IL-17 and IFN-␥. Moreover, we show that T cell activation The costs of publication of this article were defrayed in part by the payment of page induces Foxp3 expression in T cells and that the balance between charges. This article must therefore be hereby marked advertisement in accordance ϩ ϩ with 18 U.S.C. Section 1734 solely to indicate this fact. the percentage of Foxp3 and IL-17 T cells is inversely influ- enced by the cytokine environment. 1 This work was supported by Grant NS34245 from the National Institutes of Health (to C.R.-K.). 2 Address correspondence and reprint requests to Dr. Christine Rohowsky-Kochan, Materials and Methods University of Medicine and Dentistry New Jersey-New Jersey Medical School, 185 Isolation of T cell subsets South Orange Avenue, Newark, NJ 07103. E-mail address: [email protected] Research protocols were approved by the Institutional Review Board of Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 New Jersey Medical School in accordance with regulations mandated by www.jimmunol.org The Journal of Immunology 7949 the Department of Health and Human Services. Informed consent was ob- says (Applied Biosystems) and reagents were used according to the man- tained from each subject. PBMC were isolated by Ficoll-Hypaque gradient ufacturer’s instructions. Specific gene expression was normalized to the centrifugation of heparinized venous blood obtained from healthy individ- housekeeping genes GAPDH and HPRT-1. Expression of IL-17 mRNA uals. All isolations of T cell subsets were performed using magnetic beads levels was calculated by first determining the average threshold cycle (⌬Ct) and reagents from Miltenyi Biotec. CD4ϩ T cells were isolated from for each culture, which corresponded to the following: (average IL-17 PBMC by immunomagnetic depletion of non-Th cells (CD4ϩ T Cell Iso- threshold cycle Ϫ average HPRT-1 (or GAPDH) threshold cycle). Tripli- lation kit) according to the manufacturer’s instructions. Memory cate samples were used to calculate the average threshold cycle. The rep- CD45ROϩ T cells were purified from the CD4ϩ T cells using magnetic licate threshold cycle (⌬⌬Ct) was then calculated with the following for- Ͼ ⌬ Ϫ⌬ sorting with CD45RO beads, and the purity was 95% in all experiments. mula: ( Ctwith cytokine Ctwithout cytokine). IL-17 and RORC mRNA were Naive CD4ϩCD45RAϩ T cells were obtained by immunomagnetic deple- expressed as expression fold value (2Ϫ⌬⌬Ct). tion of CD45ROϩ T cells. For isolation of central and effector memory T cell subsets, CD4ϩ T cells were magnetically separated using CD45RA Statistical analysis microbeads and the CD45RAϪ fraction (CD45ROϩ) was labeled with FITC-conjugated CCR7 Ab (R&D Systems) followed by anti-FITC mi- Data were analyzed using the Statistical Package for Social Sciences soft- crobeads and passed through the magnetic sorting column. This yielded a ware program (SPSS). Data involving two groups only were analyzed us- population of purified central memory T cells (CD4ϩCD45ROϩCCR7ϩ) ing the paired Student’s t test, whereas data involving more than two ϩ ϩ Ϫ groups were analyzed using one-way ANOVA and Tukey’s multiple com- and effector memory T cells (CD4 CD45RO CCR7 ).
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