A new class of inflammatory CD4؉ T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. Interleukin-17A (IL-17A)-producing T cells are a subset of CD4 ϩ T cell lineage, termed Th17, distinct from Th1, Th2, and T regulatory (T reg ) subsets (52). IL-17 is involved in the pathogenesis of autoimmune inflammation and has been implicated in numerous autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis (MS) (10,21,26,41). IL-17 mRNA and protein levels in patients with MS have been shown to be increased in mononuclear cells isolated from blood, in cerebrospinal fluid, and in brain lesions (39,41). IL-17 is also increased in lymphocytes derived from mice with experimental autoimmune encephalomyelitis (EAE; mouse model for multiple sclerosis) (33). In IL-17A knockout (KO) mice, EAE is markedly suppressed, indicating that IL-17 contributes to the development of EAE (33). Although it has been reported that the transcription factors nuclear factor for activated T cells (NFAT), retinoid orphan nuclear receptor ␥t (ROR␥t), and Runt-related transcription factor 1 (Runx1) are important for the T cell receptor (TCR)-mediated transcriptional regulation of IL-17A (24, 29, 38, 74), knowledge of the factors involved in the cellular and molecular regulation of IL-17A remains limited.The principle function of the active form of vitamin D,, is the maintenance of calcium and phosphate homeostasis (13). However, vitamin D has numerous other functions, including downregulation of autoimmunity (7,8,25,55). 1,25(OH) 2 D 3 has been reported to at least partially protect against a number of experimental autoimmune diseases, including EAE (7,8,11,35,40,53). In addition, numerous epidemiological studies have indicated a negative correlation between increased sun exposure, which would result in a higher vitamin D synthetic rate, and diets rich in vitamin D and MS prevalence (34,55,70
Several animal autoimmune disorders are suppressed by treatment with the GM1 cross-linking units of certain toxins such as B subunit of cholera toxin (CtxB). Due to the recent observation of GM1 being a binding partner for the endogenous lectin galectin-1 (Gal-1), which is known to ameliorate symptoms in certain animal models of autoimmune disorders, we tested the hypothesis that an operative Gal-1/GM1 interplay induces immunosuppression in a manner evidenced by both in vivo and in vitro systems. Our study of murine experimental autoimmune encephalomyelitis (EAE) indicated suppressive effects by both CtxB and Gal-1 and further highlighted the role of GM1 in demonstrating enhanced susceptibility to EAE in mice lacking this ganglioside. At the in vitro level, polyclonal activation of murine regulatory T (Treg) cells caused up-regulation of Gal-1 that was both cell bound and released to the medium. Similar activation of murine CD4+ and CD8+ effector T (Teff) cells resulted in significant elevation of GM1 and GD1a, the neuraminidase-reactive precursor to GM1. Activation of Teff cells also up-regulated TRPC5 channels which mediated Ca2+ influx upon GM1 cross-linking by Gal-1 or CtxB. This involved co-cross-linking of heterodimeric integrin due to close association of these α4β1 and α5β1 glycoproteins with GM1. Short hairpin RNA (shRNA) knockdown of TRPC5 in Teff cells blocked contact-dependent proliferation inhibition by Treg cells as well as Gal-1/CtxB-triggered Ca2+ influx. Our results thus indicate GM1 in Teff cells to be the primary target of Gal-1 expressed by Treg cells, the resulting co-cross-linking and TRPC5 channel activation contributing importantly to the mechanism of autoimmune suppression.
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-α but not IL-6 and a minor subset express IL-17 with IL-22 or IL-17 and IFN-γ. 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-1β 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 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.
Accumulating evidence indicates that interleukin (IL)-27, a member of the IL-12 family of cytokines, antagonizes pathological Th17 effector cell responses. Relatively little is known about the cytokines that regulate human Th17 cells. In this study, we investigated the effect of IL-27 on the differentiation of human Th17 cells and on committed memory Th17 cells. We demonstrate that IL-27 suppresses the development of human Th17 cells by downregulating retinoid orphan nuclear receptor C expression and that this inhibition is associated with the induction of the intracellular signaling factors STAT1 and induction of the suppressor of cytokine signaling protein 1. The IL-27-mediated inhibition of IL-17 is independent of IL-10. We show that IL-27 inhibits differentiation of naïve T cells into IL-17 þ T cells under different Th17 polarizing conditions. IL-27 suppresses other Th17 subset cytokines such as IL-22 and IL-21 but not tumor necrosis factor-a. Moreover, we also show that IL-27 inhibits IL-17 production by committed Th17 memory cells, which is independent of IL-10. These studies show that IL-27 negatively regulates both the developing and committed human Th17 responses and therefore may be a promising therapeutic approach in the treatment of Th17-mediated diseases.
Previous studies have revealed the presence of Na+ / Ca2+ exchanger (NCX) activity associated with GM1 ganglioside in the nuclear envelope (NE) of neurons and glia as well as various neural cell lines. The nuclear NCX1 exchanger, unlike that in the plasma membrane, was shown to be tightly associated with GM1 and potentiated by the latter. One non-neural cell line, Jurkat, was found to contain no Na+ / Ca2+ exchanger of the NCX1, NCX2, or NCX3 types in either nuclear or plasma membrane. To determine whether such absence in the NE is generally characteristic of non-neural cells we have examined two more such cell lines in addition to human lymphocytes. RT-PCR showed NCX1 expression in both HeLa and NCTC cell lines and also NCX2 in the latter; NCX3, a subtype previously observed in NG108-15 cells, was not expressed in either. Immunocytochemical and immunoblot studies indicated NCX1 on the cell surface and nuclear envelope of both cell types. Some alternatively spliced isoforms of NCX1 in the nuclear envelope of both cell types were tightly associated with ganglioside GM1. Human lymphocytes, a mixed population of T and B cells, showed similar evidence for plasma membrane and nuclear expression in some but not all cells. The high affinity association between NCX1 and GM1, explored by reaction with base, acid, and proteases, was found to involve charge-charge interaction with a requirement for a positively charged moiety in NCX.
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