IL-22 produced by Th22 cells aggravates atherosclerosis development in ApoE−/− mice by enhancing DC-induced Th17 cell proliferation

Th22 cells are a novel subset of CD4⁺ T cells that primarily mediate biological effects through IL-22, with both Th22 cells and IL-22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE^−/− mice and age-matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL-22 among the known CD4⁺ cells, play a major role in atherosclerosis. ApoE^−/− mice fed a Western diet for 12 weeks and administered recombinant mouse IL-22 (rIL-22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3⁺ T cells, CD68⁺ macrophages, collagen, IL-6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α-actin expression than the control mice. Treatment with a neutralizing anti–IL-22 monoclonal antibody (IL-22 mAb) reversed the above effects. Bone marrow-derived DCs exhibited increased differentiation into mature DCs following rIL-22 and ox-LDL stimulation. IL-17 and pSTAT3 were up-regulated after stimulation with IL-22 and ox-LDL in cells cocultured with CD4⁺ T cells and mature DC supernatant, but this up-regulation was significantly inhibited by IL-6mAb or the cell-permeable STAT3 inhibitor S31-201. Thus, Th22 cell-derived IL-22 aggravates atherosclerosis development through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22–stimulated SMC dedifferentiation into a synthetic phenotype.     

Attenuation of migration properties of CD4+ T cells from aged mice correlates with decrease in chemokine receptor expression,response to retinoic acid,and RALDH expression compared to young mice

Aging results in attenuation of abilities to mount appropriate immune responses. The influence of aging on CD4⁺ T cell migration ability toward chemokines was investigated with young and aged mice. We found functional decline in migration ability toward CCL19 and also decreased CCR7 expression level in antigen-stimulated CD4⁺ T cells from aged mice compared with those from young mice. Upon addition of retinoic acid (RA), CD4⁺ T cells from aged mice showed decreased CCR9 expression level compared to young mice and the migration ability of CD4⁺ T cells from aged mice toward CCL25 was attenuated compared to young mice. We also observed that the expression of RALDH2 mRNA was decreased in mesenteric lymph node dendritic cells from aged mice compared to those from young mice. These results demonstrate that attenuated migration abilities of CD4⁺ T cells were observed in aged mice, which correlated with decreased chemokine receptor expression. Furthermore, the reduced production and response to RA by aging may be one of the causes of such attenuated migration abilities in the intestinal immune system.     

The tick saliva immunosuppressor, Salp15, contributes to Th17-induced pathology during Experimental Autoimmune Encephalomyelitis

Salp15 is a tick saliva protein that inhibits CD4⁺ T cell differentiation through its interaction with CD4. The protein inhibits early signaling events during T cell activation and IL-2 production. Because murine Experimental Autoimmune Encephalomyelitis development is mediated by central nervous system-infiltrating CD4⁺ T cells that are specific for myelin-associated proteins, we sought to determine whether the treatment of mice with Salp15 during EAE induction would prevent the generation of proinflammatory T cell responses and the development of the disease. Surprisingly, Salp15-treated mice developed more severe EAE than control animals. The treatment of EAE-induced mice with the tick saliva protein did not result in increased infiltration of T cells to the central nervous system, indicating that Salp15 had not affected the permeability of the blood-brain barrier. Salp15 treatment did not affect the development of antibody responses against the eliciting peptide or the presence of IFNγ in the sera. The treatment with Salp15 resulted, however, in the increased differentiation of Th17 cells in vivo, as evidenced by higher IL-17 production from PLP_139-151-specific CD4⁺ T cells isolated from the central nervous system and the periphery. In vitro, Salp15 was able to induce the differentiation of Th17 cells in the presence of IL-6 and the absence of TGFβ These results suggest that a conductive milieu for the differentiation of Th17 cells can be achieved by restriction of the production of IL-2 during T cell differentiation, a role that may be performed by TGFβ and other immunosuppressive agents.     

Cyclosporin A inhibits the production of IL-17 by memory Th17 cells from healthy individuals and patients with rheumatoid arthritis

Recent evidence from several studies indicated that IL-17-producing Th17 cells can represent the key effector cells in the induction and development of autoimmune disorders. Cyclosporine A (CsA) is a commonly used immunosuppressant to treat lots of autoimmune diseases including rheumatoid arthritis (RA). Here, we demonstrated that PBMCs and purified CD4⁺ T cells from healthy individuals and patients with RA could be induced to produce large amounts of IL-17 after stimulation with anti-CD3 plus anti-CD28 mAbs. Phenotypic analysis indicated that the majority of IL-17-producing cells were Th17 cells with memory phenotype. The addition of CsA into cell cultures significantly inhibited the IL-17 production by Th17 cells at protein and at mRNA levels. Compared to the PBMCs from normal individuals, PBMCs from the patients with RA produced higher levels of IL-17 that was also significantly inhibited by CsA both at protein and at mRNA levels. The mechanism might be the effect of CsA on the T cells activation because the expression of CD69 and CD25 molecules on T cells was markedly reduced in the presence of CsA. Taken together, these results demonstrated that CsA suppressed the IL-17 production and inhibited the Th17 cells differentiation from both healthy individuals and patients with RA.     

Dendritic cell-derived TNF-α is responsible for development of IL-10-producing CD4 T cells

Immature dendritic cells (DCs) appear to be involved in peripheral immune tolerance via induction of IL-10-producing CD4⁺ T cells. We examined the role of TNF-α in generation of the IL-10-producing CD4⁺ T cells by immature DCs. Immature bone marrow-derived DCs from wild type (WT) or TNF-α^−/− mice were cocultured with CD4⁺ T cells from OVA specific TCR transgenic mice (OT-II) in the presence of OVA_323-339 peptide. The WT DCs efficiently induced the antigen-specific IL-10-producing CD4⁺ T cells, while the ability of the TNF-α^−/− DCs to induce these CD4⁺ T cells was considerably depressed. Addition of exogenous TNF-α recovered the impaired ability of the TNF-α^−/− DCs to induce IL-10-producing T cells. However, no difference in this ability was observed between TNF-α^−/− and WT DCs after their maturation by LPS. Thus, TNF-α appears to be critical for the generation of IL-10-producing CD4⁺ T cells during the antigen presentation by immature DCs.     

Peripheral CD4CD8 cells are the activated T cells expressed granzyme B (GrB), Foxp3, interleukin 17 (IL-17), at higher levels in Th1/Th2 cytokines

Peripheral CD4⁺CD8⁺ T cells have been identified as a T cell subset existing in animals and humans. However, the characterization of CD4⁺CD8⁺ T cells, their relationship with T memory (T_M), T effector (T_E), Th1/Th2, Treg and Th-17, remain unclear. This study was to characterize the CD4⁺CD8⁺ T cells. The results from human subjects showed that activated T cells were CD4⁺CD8⁺ T cells, comprised CD4^hiCD8^lo, CD4^hiCD8^hi and CD4^loCD8^hi subsets. They expressed CD62L^hi/lo, granzyme B (GrB), CD25, Foxp3, interleukin 17 (IL-17) and the cytokines of both Th1 and Th2, and had cytolytic function. These findings suggested that CD4⁺CD8⁺ T cells had over-lap function while they kept diversity, and that T cells could be divided into two major populations: activated and inactivated. Hence, the hypotheses of Th1/Th2, Treg and Th-17 might reflect the positive/negative feedback regulation of immune system. When compared to GrB⁺CD62L^lo T effector (T_E) cells, GrB⁺CD62L^hi T central memory effector (T_CME) cells had a quicker response to virus without CD62L loss.     

Antigen-specific IL-23/17 pathway activation by murine semi-mature DC-like cells

We analyzed the phenotype and function of bone marrow-derived dendritic cells (DCs) induced in vitro without using any serum during the late stage of cultivation. These ‘serum-free’ DCs (SF-DCs) possessed the ability to induce T cell proliferation as well as antibody responses, indicating that they were functional DCs. Surprisingly, the SF-DCs akin to semi-mature DCs in terms of both phenotypic and functional characteristics. The SF-DCs did not produce IL-12 but produced large amounts of IL-23 following lipopolysaccharide stimulation. The antigen-specific production of IL-17 by CD4⁺ T cells co-cultured with OVA-loaded SF-DCs was significantly higher than that with OVA-loaded conventional DCs. These results suggest that SF-DCs tend to produce IL-23 and can consequently induce the IL-17 producing CD4⁺ T cells. The semi-mature DC-like cells reported here will be useful vehicles for DC immunization and might contribute to studies on the possible involvement of semi-mature DCs in Th17 cell differentiation.     

Increased intratumoral IL-22-producing CD4+ T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival

IL-22-producing CD4⁺ T cells (IL-22⁺CD4⁺ T cells) and Th22 cells (IL-22⁺IL-17^?IFN-γ^?CD4⁺ T cells) represent newly discovered T-cell subsets, but their nature, regulation, and clinical relevance in gastric cancer (GC) are presently unknown. In our study, the frequency of IL-22⁺CD4⁺ T cells in tumor tissues from 76 GC patients was significantly higher than that in tumor-draining lymph nodes, non-tumor, and peritumoral tissues. Most intratumoral IL-22⁺CD4⁺ T cells co-expressed IL-17 and IFN-γ and showed a memory phenotype. Locally enriched IL-22⁺CD4⁺ T cells positively correlated with increased CD14⁺ monocytes and IL-6 and IL-23 detection ex vivo, and in vitro IL-6 and IL-23 induced the polarization of IL-22⁺CD4⁺ T cells in a dose-dependent manner and the polarized IL-22⁺CD4⁺ T cells co-expressed of IL-17 and IFN-γ. Moreover, IL-22⁺CD4⁺ T-cell subsets (IL-22⁺IL-17⁺CD4⁺, IL-22⁺IL-17^?CD4⁺, IL-22⁺IFN-γ⁺CD4⁺, IL-22⁺IFN-γ^?CD4⁺, and IL-22⁺IL-17⁺IFN-γ⁺CD4⁺ T cells), and Th22 cells were also increased in tumors. Furthermore, higher intratumoral IL-22⁺CD4⁺ T-cell percentage and Th22-cell percentage were found in patients with tumor-node-metastasis stage advanced and predicted reduced overall survival. In conclusion, our data indicate that IL-22⁺CD4⁺ T cells and Th22 cells are likely important in establishing the tumor microenvironment for GC; increased intratumoral IL-22⁺CD4⁺ T cells and Th22 cells are associated with tumor progression and predict poorer patient survival, suggesting that tumor-infiltrating IL-22⁺CD4⁺ T cells and Th22 cells may be suitable therapeutic targets in patients with GC.     

Tim-3 ligand galectin-9 reduces IL-17 level and accelerates Klebsiella pneumoniae infection

T cell immunoglobulin and mucin domain (Tim)-3 is expressed on activated CD4⁺ and CD8⁺ T cells. Identification of galectin-9 as a ligand for Tim-3 has now firmly established the Tim-3/galectin-9 pathway, which results in apoptosis of effector CD4⁺ and CD8⁺ T cells. Moreover, Th17 cells are a recently discovered CD4⁺ effector T cell, which are important in antimicrobial immunity. Whether the Tim-3/galectin-9 pathway affects Th17 immunity has not been elucidated. Here, we demonstrated expression of Tim-3 on Th17 cells by flow cytometry. Th17-skewed cells were sensitive to galectin-9-induced apoptosis. In vitro administration of galectin-9 decreased stimulated Th17 cells and inhibited production of IL-17. Interestingly, Klebsiella pneumoniae (K. pneumoniae) infection led to enhanced IL-17 levels. Recombinant galectin-9 significantly decreased IL-17 in vivo, which resulted in reduced bacterial clearance and high mortality. These observations suggest that the Tim-3/galectin-9 pathway plays an important role in termination of Th17-immune responses, and could be a therapeutic target for inflammatory diseases.     

OX40 ligand regulates splenic CD8 dendritic cell-induced Th2 responses in vivo

In mice, splenic conventional dendritic cells (cDCs) can be separated, based on their expression of CD8α into CD8⁻ and CD8⁺ cDCs. Although previous experiments demonstrated that injection of antigen (Ag)-pulsed CD8⁻ cDCs into mice induced CD4 T cell differentiation toward Th2 cells, the mechanism involved is unclear. In the current study, we investigated whether OX40 ligand (OX40L) on CD8⁻ cDCs contributes to the induction of Th2 responses by Ag-pulsed CD8⁻ cDCs in vivo, because OX40–OX40L interactions may play a preferential role in Th2 cell development. When unseparated Ag-pulsed OX40L-deficient cDCs were injected into syngeneic BALB/c mice, Th2 cytokine (IL-4, IL-5, and IL-10) production in lymph node cells was significantly reduced. Splenic cDCs were separated to CD8⁻ and CD8⁺ cDCs. OX40L expression was not observed on freshly isolated CD8⁻ cDCs, but was induced by anti-CD40 mAb stimulation for 24 h. Administration of neutralizing anti-OX40L mAb significantly inhibited IL-4, IL-5, and IL-10 production induced by Ag-pulsed CD8⁻ cDC injection. Moreover, administration of anti-OX40L mAb with Ag-pulsed CD8⁻ cDCs during a secondary response also significantly inhibited Th2 cytokine production. Thus, OX40L on CD8⁻ cDCs physiologically contributes to the development of Th2 cells and secondary Th2 responses induced by Ag-pulsed CD8⁻ cDCs in vivo.     

Development of experimental cerebral malaria is independent of IL-23 and IL-17

Cerebral malaria (CM) is the most severe complication of Plasmodium infection. Although inappropriate immune responses to Plasmodium falciparum are reported as the major causes of CM, the precise mechanisms for development remain unclear. IL-23 and IL-17 have critical roles in the onset of autoimmunity and inflammatory diseases triggered by microbial infections. Thus, we investigated the influence of IL-23 and IL-17 on experimental CM (ECM) using Plasmodium berghei ANKA infection of C57BL/6 mice. Both IL-23 deficient mice and wild-type (WT) mice developed ECM. IL-17 deficient mice also developed ECM, while IL-17 producing cells other than CD4⁺ T cells (Th17) were increased in WT mice that developed ECM. In conclusion, this study showed that IL-23 and IL-17 are not involved in ECM development.     

A Marine Carotenoid,Fucoxanthin, Induces Regulatory T Cells and Inhibits Th17 Cell Differentiation in Vitro

Fucoxanthin is a non-provitamin A carotenoid contained in brown seaweeds. We found that it suppressed interleukin-17 secretion from CD4⁺ T cells under IL-17-producing T (Th17) cell development conditions. By evaluating T cell differentiation in vitro, fucoxanthin and its metabolite fucoxanthinol inhibited T cell differentiation into Th17 cells. This suggests that fucoxanthin can improve inflammatory diseases due to Th17 cells.     

Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells

Regulatory T cells (Tregs) are specialized CD4⁺ T lymphocytes helping defend against autoimmunity and inflammation. Although age is associated with increased inflammation and autoimmunity, few reports address age effects of immune regulation or auto‐aggressive T cells. We show here that young and aged naïve CD4⁺ T cells are equivalently auto‐aggressive in vivo in T cell‐driven autoimmune colitis. Young and aged CD4⁺ Tregs equally suppressed age‐matched T cell proliferation in vitro and controlled clinical and pathologic T cell‐driven autoimmune colitis, suggesting equivalent regulatory function. However, whereas young and aged CD4⁺ Tregs suppressed interferon (IFN)‐γ⁺ T cells equivalently in this model, aged CD4⁺ Tregs unexpectedly failed to restrain interleukin (IL)‐17⁺ T cells. Nonetheless, young and aged CD4⁺ Tregs equally restrained IL‐17⁺ T cells in vivo during acute inflammation, suggesting a chronic inflammation‐related defect in aged CD4⁺ Tregs. In support, aged Tregs expressed reduced STAT3 activation, a defect associated with poor IL‐17‐producing T cell restraint. Aged naïve mice had markedly increased programmed death (PD)‐1⁺ T cells, but these exhibited no significant auto‐aggressive or regulatory functions in T cell‐driven colitis. Young CD8⁺ CD122^? T cells induce autoimmune bone marrow failure, but we show that aged CD8⁺ CD122^? T cells do not. These data demonstrate no apparent age‐related increase in auto‐aggressive T cell behavior, but disclose previously unrecognized functional defects in aged CD4⁺ Tregs during chronic inflammation. IL‐17 can be inflammatory and contributes to certain autoimmune disorders. Reduced aged Treg function during chronic inflammation and reduced IL‐17 restraint could contribute to age‐related inflammation or autoimmunity.     

Cathepsin S inhibition in dendritic cells prevents Th17 cell differentiation in perivascular adipose tissues following vascular injury in diabetic rats

In the context of diabetes mellitus (DM), the circulating cathepsin S (CTSS) level is significantly higher in the cardiovascular disease group. Therefore, this study was designed to investigate the role of CTSS in restenosis following carotid injury in diabetic rats. To induce DM, 60 mg/kg of streptozotocin (STZ) in citrate buffer was injected intraperitoneally into Sprague-Dawley rats. After successful modeling of DM, wire injury of the rat carotid artery was performed, followed by adenovirus transduction. Levels of blood glucose and Th17 cell surface antigens including ROR-γt, IL-17A, IL-17F, IL-22, and IL-23 in perivascular adipose tissues (PVAT) were evaluated. For in vitro analysis, human dendritic cells (DCs) were treated with 5.6−25 mM glucose for 24 h. The morphology of DCs was observed using an optical microscope. CD4⁺ T cells derived from human peripheral blood mononuclear cells were cocultured with DCs for 5 days. Levels of IL-6, CTSS, ROR-γt, IL-17A, IL-17F, IL-22 and IL-23 were measured. Flow cytometry was conducted to detect DC surface biomarkers (CD1a, CD83, and CD86) and Th17 cell differentiation. The collected DCs presented a treelike shape and were positive for CD1a, CD83, and CD86. Glucose impaired DC viability at the dose of 35 mM. Glucose treatment led to an increase in CTSS and IL-6 expression in DCs. Glucose-treated DCs promoted the differentiation of Th17 cells. CTSS depletion downregulated IL-6 expression and inhibited Th17 cell differentiation in vitro and in vivo. CTSS inhibition in DCs inhibits Th17 cell differentiation in PVAT tissues from diabetic rats following vascular injury.     

Antagonizing dopamine D1-like receptor inhibits Th17 cell differentiation: preventive and therapeutic effects on experimental autoimmune encephalomyelitis

Five types of dopamine receptors, termed D1 to D5, have been identified to date. The D1 and D5 receptors form the D1-like group that couples with the Gαs class of G proteins, while D2, D3 and D4 form the D2-like group that couples with the Gαi class of G proteins. A D2-like-receptor (D2-like-R) antagonist L750667 induced dendritic cell (DC)-mediated Th17 differentiation. In contrast, a D1-like-R antagonist SCH23390 inhibited DC-mediated Th17 differentiation. The D1-like-Rs were expressed on both DCs and T cells, whereas D2-like-Rs were marginally expressed on CD4⁺CD45RA⁺ naïve T cells. In addition, SCH23390 had the ability to prevent experimental autoimmune encephalomyelitis (EAE) in mice. Spleen cells from EAE mice showed decreased IL-17 production, when SCH23390 was administered. Adoptive transfer of DCs treated with SCH23390 successfully prevented EAE. These findings indicate that antagonizing D1-like-Rs on DCs inhibits Th17 differentiation, thereby leading to an amelioration of EAE.     

CD103+CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis

Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4⁺ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2^-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103⁺CD11b^- DCs and increased CD103^-CD11b⁺ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1β, IL-6, IL-17, TNFα, and IFNγ combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103⁺CD11b⁺ DCs in the distal colon. CD103⁺CD11b⁺ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103^-CD11b⁺ DCs from colitic Muc2^-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103⁺CD11b⁺ DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis.     

Heterogeneity of human effector CD4+ T cells

For many years the heterogeneity of CD4⁺ T-helper (Th) cells has been limited to Th1 and Th2 cells, which have been considered not only to be responsible for different types of protective responses, but also for the pathogenesis of many disorders. Th1 cells are indeed protective against intracellular microbes and they are thought to play a pathogenic role in organ-specific autoimmune and other chronic inflammatory disorders. Th2 cells provide protection against helminths, but are also responsible for the pathogenesis of allergic diseases. The identification and cloning of new cytokines has allowed one to enlarge the series of functional subsets of CD4⁺ Th effector cells. In particular, CD4⁺ Th cells producing IL-17 and IL-22, named Th17, have been initially implicated in the pathogenesis of many chronic inflammatory disorders instead of Th1 cells. However, the more recent studies in both humans and mice suggest that Th17 cells exhibit a high plasticity toward Th1 cells and that both Th17 and Th1 cells may be pathogenic. More recently, another two subsets of effector CD4⁺ Th cells, named Th9 and Th22 cells, have been described, even if their pathophysiological meaning is still unclear. Despite the heterogeneity of CD4⁺ effector Th cells being higher than previously thought and some of their subsets exhibiting high plasticity, the Th1/Th2 paradigm still maintains a strong validity.     

Th17 and Th17-stimulated CD8<Superscript>+</Superscript> T cells play a distinct role in Th17-induced preventive and therapeutic antitumor immunity

CD4⁺ Th17 cells induce antitumor immunity leading to the eradication of established tumors. However, the mechanism of antitumour immunity and CTL activation by Th17 cells and the distinct role of Th17 and Th17-activated CTLs in antitumor immunity are still elusive. In this study, we generated ovalbumin (OVA)-specific Th17 cells by cultivating OVA-pulsed dendritic cells with CD4⁺ T cells derived from transgenic OTII mice in the presence of IL-6, IL-23, TGF-β, and anti-IFN-γ antibody. We demonstrated that Th17 cells acquired major histocompatibility complex/peptide (pMHC)-I and expressed RORγt, IL-17, and IL-2. Th17 cells did not have any direct in vitro tumor cell–killing activity. However, Th17 cells were able to stimulate CD8⁺ CTL responses via IL-2 and pMHC I, but not IL-17 signaling, which play a major role in Th17-induced preventive immunity against OVA-expressing B16 melanoma. Th17 cells stimulated the expression of CCL2 and CCL20 in lung tumor microenvironments promoting the recruitment of various inflammatory leukocytes (DCs, CD4⁺, and CD8⁺ T cells) stimulating more pronounced therapeutic immunity for early-stage (5-day lung metastases or 3 mm, s.c.) tumor than for well-established (6 mm, s.c.) tumor. The therapeutic effect of Th17 cells is associated with IL-17 and is mediated by Th17-stimulated CD8⁺ CTLs and other inflammatory leukocytes recruited into B16 melanoma via Th17-stimulated CCL20 chemoattraction. Taken together, our data elucidate a distinct role of Th17 and Th17-stimulated CD8⁺ CTLs in the induction of preventive and therapeutic antitumor immunity, which may greatly impact the development of Th17-based cancer immunotherapy.     

IL-2 limits IL-12 enhanced lymphocyte proliferation during Leishmania amazonensis infection

C3H mice infected with Leishmania amazonensis develop persistent, localized lesions with high parasite loads. During infection, memory/effector CD44^hiCD4⁺ T cells proliferate and produce IL-2, but do not polarize to a known effector phenotype. Previous studies have demonstrated IL-12 is insufficient to skew these antigen-responsive T cells to a functional Th1 response. To determine the mechanism of this IL-12 unresponsiveness, we used an in vitro assay of repeated antigen activation. Memory/effector CD44^hiCD4⁺ T cells did not increase proliferation in response to either IL-2 or IL-12, although these cytokines upregulated CD25 expression. Neutralization of IL-2 enhanced CD4⁺ T cell proliferation in response to IL-12. This cross-regulation of IL-12 responsiveness by IL-2 was confirmed in vivo by treatment with anti-IL-2 antibodies and IL-12 during antigen challenge of previously infected mice. These results suggest that during chronic infection with L. amazonensis, IL-2 plays a dominant, immunosuppressive role independent of identifiable conventional T_reg cells.     

Human Th17 cells

The discovery in mice of a new lineage of CD4⁺ effector T helper (Th) cells that selectively produce IL-17 has provided exciting new insights into immune regulation, host defence, and the pathogenesis of autoimmune and other chronic inflammatory disorders. This population of CD4⁺ Th cells, which has been termed 'Th17', indeed plays an apparently critical role in the pathogenesis of some murine models of autoimmunity. Interestingly, murine Th17 cells share a common origin with Foxp3⁺ T regulatory cells, because both populations are produced in response to transforming growth factor-β, but they develop into Th17 cells only when IL-6 is simultaneously produced. Initial studies in humans have confirmed the existence of Th17 cells, but they have shown that the origin of these cells in humans differs from that in mice, with IL-1β and IL-23 being the major cytokines responsible for their development. Moreover, the presence in the circulation and in various tissues of Th cells that can produce both IL-17 and interferon-γ, as well as the flexibility of human Th17 clones to produce interferon-γ in addition to IL-17 in response to IL-12, suggests that there may be a developmental relationship between Th17 and Th1 cells, at least in humans. Resolving this issue has great implications in tems of establishing the respective pathogenic roles of Th1 and Th17 cells in autoimmune disorders. In contrast, it is unlikely that Th17 cells contribute to the pathogenesis of human allergic IgE-mediated disorders, because IL-4 and IL-25 (a powerful inducer of IL-4) are both potent inhibitors of Th17 cell development.