Mohan S. Maddur

Th17 Cells: Biology, Pathogenesis of Autoimmune and Inflammatory Diseases, and Therapeutic Strategies

Th17 cells that secrete the cytokines IL-17A and IL-17F and express lineage-specific transcription factor RORC (RORγt in mice) represent a distinct lineage of CD4(+) T cells. Transforming growth factor-β and inflammatory cytokines, such as IL-6, IL-21, IL-1β, and IL-23, play central roles in the generation of Th17 cells. Th17 cells are critical for the clearance of extracellular pathogens, including Candida and Klebsiella. However, under certain conditions, these cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSF, and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, and allergy and asthma. This review discusses these disease states and the various therapeutic strategies under investigation to target Th17 cells, which include blocking the differentiation and amplification of Th17 cells, inhibiting or neutralizing the cytokines of Th17 cells, and suppressing the transcription factors specific for Th17 cells.

Vaccine Activation of the Nutrient Sensor GCN2 in Dendritic Cells Enhances Antigen Presentation

The Secret Life of a Vaccine Antigen-specific CD8÷ T cells play a central role in the adaptive immune response to viral infections and to cancer. Ravindran et al. (p. 313, published online 5 December) studied the successful yellow fever virus vaccine YF-17D to gain insight into its mechanism of action. The vaccine activated the nutrient deprivation sensor, GCN2 kinase, in dendritic cells. In transgenic mouse models, GCN2 activation promoted autophagy and antigen cross-presentation, enhancing the virus-specific CD8÷ T cell response. The findings suggest an important role for nutrient availability and autophagy in vaccine efficacy, which could aid more successful vaccine development. The success of the yellow fever vaccine is linked to the amino acid starvation pathway, which promotes adaptive immunity. The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D–induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8+ T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4+ and CD8+ T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.

Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy

Intravenous immunoglobulin (IVIG) is a therapeutic compound prepared from pools of plasma obtained from several thousand healthy blood donors. For more than 20 years, IVIG has been used in the treatment of a wide range of primary and secondary immunodeficiencies. IVIG now represents a standard therapeutic option for most antibody deficiencies. Routinely, IVIG is used in patients with X‐linked agammaglobulinaemia (XLA), common variable immunodeficiency (CVID), X‐linked hyper‐IgM, severe combined immunodeficiency, Wiskott‐Aldrich syndrome, and selective IgG class deficiency. In addition, IVIG is used extensively in the treatment of a wide variety of autoimmune disorders. IVIG is administered at distinct doses in the two clinical settings: whereas immunodeficient patients are treated with replacement levels of IVIG, patients with autoimmune and inflammatory diseases are administered with very high doses of IVIG. Several lines of experimental evidence gathered in the recent years suggest that the therapeutic beneficial effect of IVIG in immunodeficiencies reflects an active role for IVIG, rather than a mere passive transfer of antibodies.

Immunomodulation by Intravenous Immunoglobulin: Role of Regulatory T Cells

An altered immune homeostasis as a result of deficiency or defective function of CD4+CD25+FoxP3+ regulatory T cells (Tregs) is common in several autoimmune diseases. Hence, therapeutic strategies to render Tregs functionally competent are being investigated. Intravenous immunoglobulin (IVIG) is being increasingly used for the treatment of a wide range of autoimmune and inflammatory diseases. Recent studies have demonstrated that IVIG induces the expansion of Tregs and enhances their suppressive functions. These effects of IVIG on Tregs correlate with the beneficial effects of IVIG in patients with autoimmune diseases. Thus, modulation of Tregs by IVIG represents a novel mode of action that explains the therapeutic effects of IVIG in T cell-mediated autoimmune diseases. However, the molecular mechanisms involved in IVIG-mediated modulation of Tregs are unclear and need further investigation.

Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target.

Comparison of different IVIg preparations on IL-17 production by human Th17 cells

Variations in intravenous immunoglobulin (IVIg) products are a common feature. In this report, we compared the effect of different IVIg products on IL-17 production by human Th17 cells. We found that irrespective of products, IgGs of all IVIg preparations were equally effective in inhibiting the production of IL-17A from Th17 cells.

Circulating human basophils lack the features of professional antigen presenting cells

Recent reports in mice demonstrate that basophils function as antigen presenting cells (APC). They express MHC class II and co-stimulatory molecules CD80 and CD86, capture and present soluble antigens or IgE-antigen complexes and polarize Th2 responses. Therefore, we explored whether human circulating basophils possess the features of professional APC. We found that unlike dendritic cells (DC) and monocytes, steady-state circulating human basophils did not express HLA-DR and co-stimulatory molecules CD80 and CD86. Basophils remained negative for these molecules following stimulation with soluble Asp f 1, one of the allergens of Aspergillus fumigatus; Bet v 1, the major birch allergen; TLR2-ligand or even upon IgE cross-linking. Unlike DC, Asp f 1-pulsed basophils did not promote Th2 responses as analyzed by the secretion of IL-4 in the basophil-CD4+ T cell co-culture. Together, these results demonstrate the inability of circulating human basophils to function as professional APC.

Intravenous Gammaglobulin Inhibits Encephalitogenic Potential of Pathogenic T Cells and Interferes with their Trafficking to the Central Nervous System, Implicating Sphingosine-1 Phosphate Receptor 1–Mammalian Target of Rapamycin Axis

Despite an increasing use of high-dose therapy of i.v. gammaglobulin (IVIg) in the treatment of various T cell– and Ab-mediated inflammatory and autoimmune diseases, comprehension of the mechanisms underlying its therapeutic benefit has remained a major challenge. Particularly, the effect of IVIg in T cell–mediated autoimmune conditions remains unexplored. Using an actively induced experimental autoimmune encephalomyelitis model, a T cell–mediated autoimmune condition, we demonstrate that IVIg inhibits the differentiation of naive CD4 T cells into encephalitogenic subsets (Th1 and Th17 cells) and concomitantly induces an expansion of Foxp3+ regulatory T cells. Further, IVIg renders effector T cells less pathogenic by decreasing the expression of encephalitogenic molecular players like GM-CSF and podoplanin. Intriguingly and contrary to the current arguments, the inhibitory FcγRIIB is dispensable for IVIg-mediated reciprocal modulation of effector and regulatory CD4 subsets. Additionally, F(ab′)2 fragments also retained this function of IVIg. IVIg or F(ab′)2 fragments decrease the sphingosine-1 phosphate receptor on CD4 cells, thus sequestering these cells in the draining lymph nodes and decreasing their infiltration into the CNS. Our study reveals a novel role of Igs in the modulation of polarization and trafficking of T lymphocytes, accounting for the observed beneficial effect in IVIg therapy.

Human B cells induce dendritic cell maturation and favour Th2 polarization by inducing OX-40 ligand

Dendritic cells (DCs) play a critical role in immune homeostasis by regulating the functions of various immune cells, including T and B cells. Notably, DCs also undergo education on reciprocal signalling by these immune cells and environmental factors. Various reports demonstrated that B cells have profound regulatory functions, although only few reports have explored the regulation of human DCs by B cells. Here we demonstrate that activated but not resting B cells induce maturation of DCs with distinct features to polarize Th2 cells that secrete interleukin (IL)-5, IL-4 and IL-13. B-cell-induced maturation of DCs is contact dependent and implicates signalling of B-cell activation molecules CD69, B-cell-activating factor receptor, and transmembrane activator and calcium-modulating cyclophilin ligand interactor. Mechanistically, differentiation of Th2 cells by B-cell-matured DCs is dependent on OX-40 ligand. Collectively, our results suggest that B cells have the ability to control their own effector functions by enhancing the ability of human DCs to mediate Th2 differentiation.

Mycobacterium tuberculosis Promotes Regulatory T-Cell Expansion via Induction of Programmed Death-1 Ligand 1 (PD-L1, CD274) on Dendritic Cells

To the Editor—CD4CD25FoxP3 regulatory T cells (Tregs) are critical for the maintenance of immune tolerance by suppressing immune cell functions. In the context of infection such as Mycobacterium tuberculosis, Tregs can also suppress efficient protective immune responses against the pathogen and its effective clearance [1]. Results from studies of patients with tuberculosis and experimental models have shown that Tregs are expanded and accumulated at the site of infection. These Tregs efficiently inhibit the arrival of effector T cells in the lungs, production of interferon (IFN)–c and cd T-cell responses to M. tuberculosis [2–4]. However, mechanisms underlying the expansion of Tregs are not clear. Periasamy et al [5] identified that Treg expansion by M. tuberculosis requires expression of the protein programmed death-1 (PD-1, CD279). Inhibition of PD-1 by blocking antibodies or small interfering RNA prevented the Treg expansion. However, the questions that remain unanswered are as follows: does M. tuberculosis trigger dynamic changes in the expression of signaling molecules on innate immune cells that, in turn, facilitate Treg expansion, and if so, which innate pattern recognition receptors are implicated in this process? Because Treg expansion in the periphery requires costimulatory signals and antigen presentation by antigen-presenting cells such as dendritic cells (DCs), we surmised that the Treg expansion observed by the Periasamy et al [5] might reflect the modulation of DCs by M. tuberculosis. After education by M. tuberculosis, these DCs then might provide signals for expansion of Tregs. To address our hypothesis, immature DCs were derived by culturing peripheral blood monocytes (isolated by using CD14 microbeads; Miltenyi Biotec) from healthy blood donors after ethical committee permission, in the presence of granulocyte microphage colonystimulating factor (GM-CSF; 1000 IU/10 cells) and IL-4 (500 IU/10 cells). The 5-day-old immature DCs (0.5x10/ml) were either cultured in the presence of cytokines alone or cytokines plus whole cell lysates (WCLs) of pathogenic M. tuberculosis H37Rv (5 microgram/mL) for 48 h. The DCs were washed thoroughly and were cocultured with 0.2 3 106 CD4 1 T cells at 1:10 ratio for 96 h. CD4 T cells were isolated by using CD4 microbeads. The DCs and CD4 T cells were from unrelated donors, and hence CD3 and CD28 stimulation was not provided. The frequency of CD4CD25FoxP3 Tregs was analyzed using flow cytometry (LSR II, BD Biosciences). Surface staining was performed with fluorochrome-conjugated monoclonal antibodies (MAbs) to CD4 and CD25 (BD Biosciences), and intracellular staining for FoxP3 was performed using fluorochrome-conjugated MAb to FoxP3 and kit from eBioscience. We found that M. tuberculosis–treated DCs significantly expand Tregs (3.5% 6 0.5% in control vs 6.6% 6 0.8% in M. tuberculosis–treated DCs; n 5 5; Figure 1A). The results suggest that the Treg expansion observed by Periasamy et al [5] was indeed attributable to modulation of DC (or innate immune cells in general) functions by M. tuberculosis.