T helper (Th) cell profiles and cytokines/chemokines in characterization, treatment, and monitoring of autoimmune diseases.

Autoimmune diseases (AD) consist of a spectrum of disease entities whose etiologies are very complex and still not well understood. Every individual has the potential for developing AD under appropriate conditions because the body contains lymphocytes that are potentially reactive with self-antigens. The aims of this study are to (1) explore the flow cytometry method to identify the frequency of various circulating CD4+ T helper (Th) cell-subsets, including Th1, Th2, Th9, Th17, Th17.1, and Th22; (2) In parallel, to examine multiplex ELISA method for pathogenic inflammatory cytokines/chemokines, and (3) To assess the correlation of expression of T cell-subsets with serum cytokines/chemokines and understand its clinical importance with available AD treatments. We analyzed Th17, Th17.1, Th22, Th2, Th1, and Th9 Th cell populations and compared the concentrations of 67 cytokines/chemokines in healthy as well as AD-diagnosed patients. We observed that patients with autoimmune markers had significantly elevated percentages of naïve (Th17, Th22, and Th9) as well as memory (Th17 and Th22) Th cell-subsets, along with increased concentrations of cytokines/chemokines (Eotaxin, TNFß, and FABP4). The percentage of Th cell-subsets correlated positively or negatively with the production of cytokines/chemokines of patients diagnosed with AD. Our study demonstrates that the naïve and memory Th cell-subsets with positive correlations to cytokines/chemokines show new diagnostic markers to predict the patients' outcome, while the negative correlation of cytokines/chemokines shows the response to autoimmune therapies. Our findings of Th cell-subsets by flow cytometry and cytokines/chemokines by multiplex ELISA suggest that CCR6+ Th cell-subsets (Th17, Th17.1, Th22, and Th9) contribute to our understanding of the pathogenesis of AD and identify the new onset of AD from the autoimmune spectrum. Our findings highlight the importance of CCR6+ as a possible marker in the characterization, treatment, and monitoring of AD.

Decreased frequency of Th22 cells and IL-22 cytokine in kidney transplant patients with active cytomegalovirus infection.

BACKGROUND: The immunity of CD4+ T cell subsets against human cytomegalovirus (HCMV) is considerable due to their essential role in controlling the infection in transplant individuals. Previously explained CD4+ subsets such as T helper (Th) 1 have been proven to have a protective role against HCMV infection, while the role of the recently identified Th22 subset has not been described yet. Here, the frequency changes of Th22 cells and the IL-22 cytokine production were investigated in kidney transplant recipients with and without HCMV infection. METHODS: Twenty kidney transplant patients and ten healthy controls were enrolled in this study. Patients were categorized into HCMV + and HCMV- groups based on the HCMV DNA real-time PCR results. After isolating CD4+ T cells from PBMCs, the phenotype (CCR6+CCR4+CCR10+) and cytokine profile (IFN-γ-IL-17-IL-22+) of Th22 cells were analyzed by flow cytometry. The gene expression of Aryl Hydrocarbon Receptor (AHR) transcription factor was analyzed by real-time PCR. RESULTS: The phenotype frequency of these cells was lower in recipients with infection than in those without infection and healthy controls (1.88 ± 0.51 vs. 4.31 ± 1.05; P = 0.03 and 4.22 ± 0.72; P = 0.01, respectively). A lower Th22 cytokine profile was observed in patients with infection than in the two other groups (0.18 ± 0.03 vs. 0.20 ± 0.03; P = 0.96 and 0.33 ± 0.05; P = 0.04, respectively). AHR expression was also lower in patients with active infection. CONCLUSIONS: Overall, this study for the first time suggests that the reduced levels of Th22 subset and IL-22 cytokine in patients with active HCMV infection might indicate the protective role of these cells against HCMV.

IL-22 as a target for therapeutic intervention: Current knowledge on its role in various diseases.

IL-22 has emerged as a crucial cytokine mediating protective response against pathogens and tissue regeneration. Dysregulated production of IL-22 has been shown to play a pivotal role in the pathogenesis of various diseases like malignant tumours, viral, cardiovascular, allergic and autoimmune disorders. Interleukin 22 belongs to IFN-IL-10 cytokine family. It is a major proinflammatory cytokine secreted by activated Th1 cells (Th22), though can also be secreted by many other immune cells like group 3 innate lymphocytes, γδ T cells, NK cells, NK T cells, and mucosal associated invariant T cells. Th22 cells exclusively release IL-22 but not IL-17 or IFN-γ (as Th1 cells releases IFN-γ along with IL-22 and Th17 cells releases IL-17 along with IL-22) and also express aryl hydrocarbon receptor as the key transcription factor. Th22 cells also exhibit expression of chemokine receptor CCR6 and skin-homing receptors CCR4 and CCR10 indicating the involvement of this subset in bolstering epithelial barrier immunity and promoting secretion of antimicrobial peptides (AMPs) from intestinal epithelial cells. The function of IL-22 is modulated by IL-22 binding protein (binds to IL-22 and inhibits it binding to its cell surface receptor); which serves as a competitor for IL-22R1 chain of IL-22 receptor. The pathogenic and protective nature of the Th22 cells is modulated both by the site of infected tissue and the type of disease pathology. This review aims to discuss key features of IL-22 biology, comparisons between IL and 22 and IFN-γ and its role as a potential immune therapy target in different maladies.

CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn's disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of interactions among other immune cells that modulate the further progression of IBD. This review examines the role of the CD4 T-cells most relevant to IBD, highlighting how these cells adapt to the environment and interact with other cell populations to promote or inhibit the development of IBD.

Th22 cells induce Müller cell activation via the Act1/TRAF6 pathway in diabetic retinopathy.

T helper 22 (Th22) cells have been implicated in diabetic retinopathy (DR), but it remains unclear whether Th22 cells involve in the pathogenesis of DR. To investigate the role of Th22 cells in DR mice, the animal models were established by intraperitoneal injection of STZ and confirmed by fundus fluorescein angiography and retinal haematoxylin-eosin staining. IL-22BP was administered by intravitreal injection. IL-22 level was measured by ELISA in vivo and in vitro. The expression of IL-22Rα1 in the retina was assessed by immunofluorescence. We assessed GFAP, VEGF, ICAM-1, inflammatory-associated factors and the integrity of blood-retinal barrier in control, DR, IL-22BP, and sham group. Müller cells were co-cultured with Th22 cells, and the expression of the above proteins was measured by immunoblotting. Plasmid transfection technique was used to silence Act1 gene in Müller cells. Results in vivo and in vitro indicated that Th22 cells infiltrated into the DR retinal and IL-22Rα1 expressed in Müller cells. Th22 cells promoted Müller cells activation and inflammatory factor secretion by secreting IL-22 compared with high-glucose stimulation alone. In addition, IL-22BP ameliorated the pathological alterations of the retina in DR. Inhibition of the inflammatory signalling cascade through Act1 knockdown alleviated DR-like pathology. All in all, the results suggested that Th22 cells infiltrated into the retina and secreted IL-22 in DR, and then IL-22 binding with IL-22Rα1 activated the Act1/TRAF6 signal pathway, and promoted the inflammatory of Müller cells and involved the pathogenesis of DR.

Th22 cytokines and yellow fever: Possible implications for the immunopathogenesis of human liver infection.

Yellow fever (YF) is an infectious disease considered a public health problem in tropical and subtropical areas. YF has many pathophysiological events that are correlated with the host immune response. In this study, the in situ Th22 cytokine profile was evaluated. Liver tissue samples were collected from 21 YFV-positive patients who died of the disease and five flavivirus-negative controls who died of other causes and whose hepatic parenchyma architecture was preserved. Immunohistochemical (IHC) analysis of tissues in the hepatic parenchyma of YF cases showed significantly higher expression of interleukin (IL)-22, IL-13, tumour necrosis factor-alpha, and FGF basic (FGF b) in YFV-positive cases than that in flavivirus-negative controls. These results indicate that the response of Th22 cytokines emerges as an alternative for a better understanding of adaptive immunity in the hepatic parenchyma, highlighting the role of cytokines in the repair and suppressive responses in the immunopathogenesis of YFV infection.

The role of Th22 cells, from tissue repair to cancer progression.

CD4+ T helper (Th) cells play a significant role in modulating host defense. In the presence of lineage specific cytokine cocktail, Naive CD4+ T cells can differentiate into several categories with distinct cytokines profile and effector functions. Th22 cells are a recently identified subset of CD4+ T cell, which differentiate from Naive CD4+ T in the presence of IL-6 and TNF-α. Th22 characterized by the production of interleukin-22 (IL-22) and expression of aryl hydrocarbon receptor (AHR). The main function of Th22 cells is to participate in mucosal defense, tissue repair, and wound healing. However, controversial data have shown that overexpression of IL-22 can lead to pathological changes under inflammatory conditions and tumor progression. This review summarizes our knowledge about the role of Th22 and IL-22 cells in tumor progression through induction of inflammation.

Skin Treatment with Detergent Induces Dermatitis with H1-Antihistamine-Refractory Itch and Upregulates IL-4 and Th17/Th22 Cytokine Gene Expression in C57BL/6 Mice.

INTRODUCTION: Repeated skin contact to detergents causes chronic irritant contact dermatitis (ICD) associated with itch sensation and eczema. However, the mechanisms of detergent-induced ICD are poorly understood. Here, we established a new murine model of detergent-induced ICD with H1-antihistamine-refractory itch. METHODS: Ear skin of wild-type and mast cell-deficient mice on the C57BL/6 genetic background was treated with a detergent, sodium dodecyl/lauryl sulfate (SDS), daily for approximately 2 weeks with or without administration of an H1-antihistamine, fexofenadine. Skin inflammation, barrier dysfunction, and itching were analyzed. Quantitative PCR for earlobe gene expression and flow cytometry analysis for draining lymph node cells were conducted. RESULTS: SDS treatment induced skin inflammation with ear swelling, increased transepidermal water loss, and hind-paw scratching behaviors in the wild-type and mast cell-deficient mice. The peak value of scratching bouts was retained for at least 48 h after the last SDS treatment. H1-antihistamine administration showed no or little reduction in the responses. SDS treatment upregulated gene expression for a Th2 cytokine IL-4 and Th17/Th22 cytokines, IL-17A, IL-17F, and IL-22, and increased cell numbers in draining lymph nodes of CD4+ T, CD8+ T, and γδT cells with enhanced expression of GATA3, RORγt, T-bet, or FOXP3 compared with untreated mice. CONCLUSIONS: The present study showed that SDS treatment of ear skin in C57BL/6 mice induces mast cell-independent skin inflammation with H1-antihistamine-refractory itch and suggested a possible Th cytokine- and/or lymphocyte-mediated regulation of the model. The model would be useful for elucidation of mechanisms for inflammation with H1-antihistamine-refractory itch in detergent-induced ICD.

Caspase-1 inhibition by YVAD generates tregs pivoting IL-17 to IL-22 response in ß-glucan induced airway inflammation.

BACKGROUND: During Aspergillus fumigatus mediated lung inflammation, NLRP3 inflammasome is rapidly activated that aggravates IL-1ß production contributing to lung inflammation. Previously, we have shown the protective role of SYK-1 inhibition in inhibiting inflammasome activation during lung inflammation. In the current manuscript, we explored the protective role of direct caspase-1 inhibition during ß-glucan-induced lung inflammation. METHODS: We have mimicked the lung inflammation by administering intranasal ß-glucan in mice model. YVAD was used for caspase-1 inhibition. RESULTS: We have shown that caspase-1 inhibition by YVAD did not alter inflammasome independent inflammatory cytokines, while it significantly reduced inflammasome activation and IL-1ß secretion. Caspase-1 inhibited bone marrow derived dendritic cells (BMDCs), co-cultured with T cells showed decreased T-cell proliferation and direct them to secrete high TGF-ß and IL-10 compared to the T cells co-cultured with ß-glucan primed dendritic cells. Caspase-1 inhibition in BMDCs also induced IL-22 secretion from CD4+T cells. Caspase-1 inhibition in intranasal ß-glucan administered mice showed decreased tissue damage, immune cell infiltration and IgA secretion compared to control mice. Further, splenocytes challenged with ß-glucan show high IL-10 secretion and increased FOXp3 and Ahr indicating an increase in regulatory T cells on caspase-1 inhibition. CONCLUSION: Caspase-1 inhibition can thus be an attractive target to prevent inflammation mediated tissue damage during Aspergillus fumigatus mouse model and can be explored as an attractive therapeutic strategy.HIGHLIGHTSCaspase-1 inhibition protects lung damage from inflammation during ß-glucan exposureCaspase-1 inhibition in dendritic cells decreases IL-1ß production resulting in decreased pathogenic Th17Caspase-1 inhibition promotes regulatory T cells thereby inhibiting lung inflammation.

IgG from Adult Atopic Dermatitis (AD) Patients Induces Thymic IL-22 Production and CLA Expression on CD4+ T Cells: Possible Epigenetic Implications Mediated by miRNA.

Atopic dermatitis (AD) is a common relapsing inflammatory skin disorder characterized by immune-mediated inflammation and epidermal barrier dysfunction. The pathogenesis of AD is multifactorial and has not been fully elucidated to date. This study aimed to evaluate whether serum IgG from adult AD patients could modulate the thymic maturation of IL-22-producing T cells and CLA+ T cells of non-atopic infants. Given that miRNAs regulate immune response genes, we evaluated whether miRNA expression is also altered in cultured thymocytes. Thymocytes were cultured with purified IgG from AD patients or control conditions (mock, Intravenous-IgG (IVIg), non-atopic IgG, or atopic non-AD IgG). Using flow cytometry analysis, we assessed the expression of CLA and intracellular levels of IL-4, IFN-γ, and IL-22 on double-positive T cells (DP T), CD4 T cells, or CD8 T cells. We also investigated the frequency of IgG isotypes and their direct interaction with the thymic T cells membrane. The miRNA profiles were evaluated by the Illumina small RNA-seq approach. MiRNA target gene prediction and enrichment analyses were performed using bioinformatics. Increased frequencies of IL-22 and CLA+ producing CD4+ T cells cultured with IgG of AD patients was seen in non-atopic infant thymocytes compared to all control conditions. No alterations were observed in the frequency of IgG isotypes among evaluated IgG pools. Evidence for a direct interaction between IgG and thymic DP T, CD4 T, and CD8 T cells is presented. The small RNA-seq analysis identified ten mature miRNAs that were modulated by AD IgG compared to mock condition (miR-181b-5p, hsa-miR-130b-3p, hsa-miR-26a-5p, hsa-miR-4497, has-miR-146a, hsa-let-7i-5p, hsa-miR-342-3p, has-miR-148a-3p, has-miR-92a and has-miR-4492). The prediction of the targetome of the seven dysregulated miRNAs between AD and mock control revealed 122 putative targets, and functional and pathway enrichment analyses were performed. Our results enhance our understanding of the mechanism by which IgG can collaborate in thymic T cells in the setting of infant AD.

Th22 response induced by Mycobacterium tuberculosis strains is closely related to severity of pulmonary lesions and bacillary load in patients with multi-drug-resistant tuberculosis.

The role of interleukin-22 (IL-22) in the pathogenesis or tissue repair in human tuberculosis (TB) remains to be established. Here, we aimed to explore the ex-vivo and in-vitro T helper 22 (Th22) response in TB patients and healthy donors (HD) induced by different local multi-drug-resistant (MDR) Mvcobacterium tuberculosis (Mtb) strains. For this purpose, peripheral blood mononuclear cells from drug-susceptible (S-TB) MDR-TB patients and HD were stimulated with local MDR strains and the laboratory strain H37Rv. IL-22 and IL-17 expression and senescent status were assessed in CD4+ and CD8+ cells by flow cytometry, while IL-22 amount was measured in plasma and culture supernatants by enzyme-linked immunosorbent assay (ELISA). We found lower IL-22 amounts in plasma from TB patients than HD, together with a decrease in the number of circulating T cells expressing IL-22. In a similar manner, all Mtb strains enhanced IL-22 secretion and expanded IL-22+ cells within CD4+ and CD8+ subsets, being the highest levels detected in S-TB patients. In MDR-TB, low systemic and Mtb-induced Th22 responses associated with high sputum bacillary load and bilateralism of lung lesions, suggesting that Th22 response could be influencing the ability of MDR-TB patients to control bacillary growth and tissue damage. In addition, in MDR-TB patients we observed that the higher the percentage of IL-22+ cells, the lower the proportion of programmed cell death 1 (PD-1)+ or CD57+ T cells. Furthermore, the highest proportion of senescent T cells was associated with severe lung lesions and bacillary load. Thus, T cell senescence would markedly influence Th22 response mounted by MDR-TB patients.

Dynamic alterations and durability of T helper 22 and its corresponding cytokines following treatment in pediatric visceral leishmaniasis.

Considering the collaboration between immune responses and medications for the improvement of visceral leishmaniasis (VL), this study investigated the levels of T helper (Th) 22 and the corresponding cytokines in the acute phase of VL and their alterations following treatment. The study was conducted on 18 patients with confirmed VL and 20 healthy sex and age matched children as the controls. The levels of Th22 cells and the cytokines driving their differentiations and functions in the blood and peripheral blood mononuclear cells (PBMC) cultured supernatants, were assessed using flow cytometry method. The results revealed significantly higher levels of Th22, IL-21 and IL-6 in the patients' blood than those in the controls. Additionally, higher levels of IL-21 and IL-22 were observed in the cultured supernatants of VL patients' PBMCs, compared to the controls. Upon treatment, Th22 and IL-6 were down-regulated and conversely, IL-21, IL-22, IL-23 and IL-33 were significantly up-regulated in the patients' blood at different time points. Receiver operating characteristic (ROC) curve analysis indicated that for the differential diagnosis of VL, plasma IL-21 is more sensitive and specific than Th22 and the above mentioned cytokines. The higher proportions of Th22 and IL-21 in the VL patients and their alterations post treatment confer their roles in the immunopathogenesis of VL. So, Th22 and IL-21 in the patients' blood can be considered as biomarkers to be used for the differential diagnosis of VL. Nevertheless, further studies are warranted to clarify their particular mechanisms in this process.

Circulating Th22 cells, as well as Th17 cells, are elevated in patients with renal cell carcinoma.

T-helper (Th) 22 cells serve an essential role in different types of tumors and autoimmune diseases. No research has been conducted to study the role of Th22 cells in the pathogenesis of renal cell carcinoma (RCC). We aimed to evaluate the prognostic value of circulating Th22, Th17, and Th1 cells in RCC patients. Thirty-two newly diagnosed RCC patients and thirty healthy controls were enlisted in the research. Their peripheral blood was collected, and the frequencies of circulating Th22, Th17, and Th1 cells were detected by flow cytometry. Plasma IL-22 concentrations were examined by an enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to identify the mRNA expression levels of aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) in peripheral blood mononuclear cells (PBMC). Compared with the healthy control group, the frequency of circulating Th22 and Th17 cells and concentrations of plasma IL-22 were significantly increased in RCC patients. However, there was no significant difference in the frequency of Th1 cells. A positive correlation between Th22 cells and plasma IL-22 levels was found in RCC patients. Also, there was a significant positive correlation between Th22 and Th17 cells in RCC patients. An up-regulated expression of AHR and RORC transcription factors were also observed in RCC patients. As tumor stage and grade progressed, the frequencies of Th22 and Th17 cells and the level of plasma IL-22 significantly increased. Meanwhile, there was a positive correlation between Th22 and Th17 cells and RCC tumor stage or grade. Furthermore, patients with high Th22 or Th17 cells frequency displayed a decreased trend in survival rate. Our research indicated that the increased circulating Th22 and Th17 cells and plasma IL-22 may be involved in the pathogenesis of RCC and may be involved in the occurrence and development of tumors. Th22 cells, plasma IL-22, and Th17 cells may be promising new clinical biomarkers and may be used as cellular targets for RCC therapeutic intervention.

The NOTCH-HES-1 axis is involved in promoting Th22 cell differentiation.

BACKGROUND: NOTCH signaling has been shown to play a role in the production of interleukin-22 (IL-22) by CD4+ T cells. Multiple T-helper (Th) cell populations secrete IL-22. Th22 (CD4+IL22+IFNγ-IL17A-) cells are a subgroup of CD4+ effector T cells that primarily generate IL-22. The regulatory mechanisms of the NOTCH signaling pathway involved in differentiation of the Th22 cell subset have not been completely elucidated. This study aimed to further explore the involvement of NOTCH signaling in Th22 differentiation. METHODS: In vitro combination of IL-6, IL-23, and tumor necrosis factor-α (TNF-α) treatment with naïve CD4+ T cells established the Th22 cell induced model. NOTCH signaling was activated by jagged-1 and inhibited by (2S)-N-[(3,5-difluorophenyl) acetyl]-L-alanyl-2-phenyl]glycine 1,1-dimethylethyl ester (DAPT). HES-1 siRNA and HES-1 vector were employed to knock down and induce overexpression of HES-1 to investigate the effect of NOTCH signaling on the differentiation of CD4+T cells into Th22 cells. RESULTS: We observed that the proportion of Th22 cells, along with Hes-1, Ahr, and Il-22 mRNA and protein expression, was increased by both jagged-1 and overexpression of HES-1. On the other hand, after the combined cytokine treatment of cells, and exposure to jagged-1 and DAPT or HES-1 siRNA, there was a decrease in the Th22 cell proportion, mRNA and protein expression of HES-1, AHR, and IL-22. CONCLUSIONS: Our study demonstrates that HES-1 enhancement in AHR and IL-22 up-regulation of NOTCH signaling can promote the skewing of naïve CD4+T cells toward Th22 cells. Also, the results of our study show that HES-1 is a crucial factor in Th22 cell differentiation.

Decreased Expression of Sirt1 Contributes to Ocular Behçet's Disease Progression via Th17 and Th22 Response.

BACKGROUND: Previous studies have indicated that Sirtuin 1 (Sirt1) plays an important role in suppressing inflammatory responses in many diseases. However, the Sirt1 levels and role of Sirt1 in ocular Behçet's disease (OBD) have not been fully elucidated. OBJECTIVE: The objective of this study was to investigate the role of Sirt1 in the pathogenesis of OBD. METHODS: Sirt1 and cytokine levels were measured using ELISA. Cell viability was determined using the Cell Counting Kit-8. The frequencies of Th17 and Th22 cells were detected using flow cytometry. RESULTS: We found decreased expression of Sirt1 in CD4+ T cells obtained from patients with active OBD. SRT1720, an agonist of Sirt1, significantly upregulated Sirt1 expression in CD4+ T cells from patients with active OBD. Sirt1 activation by SRT1720 significantly suppressed the production of interleukin (IL)-17 and IL-22 by CD4+ T cells and inhibited the expansion of Th17 and Th22 cells. CONCLUSION: Our results suggest that decreased Sirt1 expression might be involved in the pathogenesis of OBD and that activation of Sirt1 might be considered a potential target for OBD.

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.

Limited Role of Mincle in the Host Defense against Infection with Cryptococcus deneoformans.

Cryptococcus deneoformans is an opportunistic fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired cell-mediated immune responses such as AIDS. Caspase-associated recruitment domain 9 (CARD9) plays a critical role in the host defense against cryptococcal infection, suggesting the involvement of one or more C-type lectin receptors (CLRs). In the present study, we analyzed the role of macrophage-inducible C-type lectin (Mincle), one of the CLRs, in the host defense against C. deneoformans infection. Mincle expression in the lungs of wild-type (WT) mice was increased in the early stage of cryptococcal infection in a CARD9-dependent manner. In Mincle gene-disrupted (Mincle KO) mice, the clearance of this fungus, pathological findings, Th1/Th2 response, and antimicrobial peptide production in the infected lungs were nearly comparable to those in WT mice. However, the production of interleukin-22 (IL-22), tumor necrosis factor alpha (TNF-α), and IL-6 and the expression of AhR were significantly decreased in the lungs of Mincle KO mice compared to those of WT mice. In in vitro experiments, TNF-α production by bone marrow-derived dendritic cells was significantly decreased in Mincle KO mice. In addition, the disrupted lysates of C. deneoformans, but not those of whole yeast cells, activated Mincle-triggered signaling in an assay with a nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Mincle may be involved in the production of Th22-related cytokines at the early stage of cryptococcal infection, although its role may be limited in the host defense against infection with C. deneoformans.

CD4+ T cell phenotypes in the pathogenesis of immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts due to enhanced platelet clearance and compromised production. Traditionally, ITP was regarded a B cell mediated disorder as anti-platelet antibodies are detected in most patients. The very nature of self-antigens, evident processes of isotype switching and the affinity maturation of anti-platelet antibodies indicate that B cells in order to mount anti-platelet immune response require assistance of auto-reactive CD4+ T cells. For a long time, ITP pathogenesis has been exclusively reviewed through the prism of the disturbed balance between Th1 and Th2 subsets of CD4+ T cells, however, more recently new subsets of these cells have been described including Th17, Th9, Th22, T follicular helper and regulatory T cells. In this paper, we review the current understanding of the role and immunological mechanisms by which CD4+ T cells contribute to the pathogenesis of ITP.

Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases.

Prostaglandins (PGs) are the major lipid mediators in animals and which are biosynthesized from arachidonic acid by the cyclooxygenases (COX-1 or COX-2) as the rate-limiting enzymes. Prostaglandin E2 (PGE2), which is the most abundantly detected PG in various tissues, exerts versatile physiological and pathological actions via four receptor subtypes (EP1-4). Non-steroidal anti-inflammatory drugs, such as aspirin and indomethacin, exert potent anti-inflammatory actions by the inhibition of COX activity and the resulting suppression of PG production. Therefore, PGE2 has been shown to exacerbate several inflammatory responses and immune diseases. Recently, studies using mice deficient in each PG receptor subtype have clarified the detailed mechanisms underlying PGE2-associated inflammation and autoimmune diseases involving each EP receptor. Here, we review the recent advances in our understanding of the roles of PGE2 receptors in the progression of acute and chronic inflammation and autoimmune diseases. PGE2 induces acute inflammation through mast cell activation via the EP3 receptor. PGE2 also induces chronic inflammation and various autoimmune diseases through T helper 1 (Th1)-cell differentiation, Th17-cell proliferation and IL-22 production from Th22 cells via the EP2 and EP4 receptors. The possibility of EP receptor-targeted drug development for the treatment of immune diseases is also discussed.

Increased Th17 and Th22 Cell Percentages Predict Acute Lung Injury in Patients with Sepsis.

PURPOSE: This study was conducted to investigate the percentages of Th22 and Th17 cells in the peripheral blood of septic patients with and without acute lung injury (ALI) and their clinical significance. METHODS: A total of 479 patients were divided into non-ALI and ALI groups. The percentages of Th22 and Th17 cells and the levels of interleukin 22 (IL-22), 6 (IL-6), and 17 (IL-17) were determined. Receiver operating characteristic curve analysis was performed to assess the diagnostic value of Th22 and Th17 cells to predict sepsis-induced ALI. RESULTS: The lung injury prediction score (LIPS), IL-6, IL-17, and IL-22 levels and the percentages of Th17 and Th22 cells were significantly higher in the ALI group (P < 0.05). They were significant factors affecting sepsis-induced ALI (P < 0.05). Multivariate logistic regression analysis showed that the LIPS (OR = 1.130), IL-17 (OR = 1.982), IL-22 (OR = 2.612) and the percentages of Th17 (OR = 2.211) and Th22 (OR = 3.230) cells were independent risk factors for ALI. The area under the curve of Th22 cells was 0.844 to predict ALI with a cutoff value of 6.81%. The sensitivity and specificity for early diagnosis of sepsis-induced ALI by the Th22 cell percentage were 78.72% and 89.13%, respectively. CONCLUSIONS: Th22 and Th17 cells in peripheral blood are significantly increased in septic patients with ALI and they may be used as biomarkers for early diagnosis of sepsis-induced ALI.