Novel Subset Of CD4 Research Articles

Contribution of T helper 17 cells and interleukin-17 to the pathogenesis of primary immune thrombocytopenia in Egyptian children

Though pathogenesis of primary immune thrombocytopenia (ITP) is still rendered unclear, yet there are many research efforts that have been directed to the role of T helper 17 (Th17) and interleukin 17 (IL-17) in the pathogenesis of this disease. The Th17 cell, which produces IL-17, is a subset of T helper cells. Interleukin 17 is pro-inflammatory cytokine that is recently proved to have a crucial role in the emergence of autoimmune diseases. We aimed to investigate the role of T helper17 cells and interleukin-17 in the pathogenesis of ITP in Egyptian children. This study was carried out on 100 children with ITP and 100 apparently healthy children as a control group. Patients were subjected to full medical history taking, thorough physical examination and routine investigations according to our local standards. Percentage of Th17 cells was measured by flow cytometry in study groups. Also, serum IL-17 was measured in in study groups by ELISA. Th 17 cells were significantly higher in patients compared to controls. Moreover, 3.1-fold increased serum levels of IL-17 were observed in patients with ITP compared to controls. Newly diagnosed patients had significantly higher percentage of Th-17cells as well as higher IL-17 levels than patients with either persistent or chronic ITP. Conclusion: We concluded that Th 17 cells and IL-17 seem to play an important role in the pathogenesis of ITP in Egyptian children.What is Known -- What is New:• The pathogenesis of ITP is heterogeneous A novel subset of CD4+ T cells, distinct from Th1 and Th2, was recently identified. It is characterized by the production of IL-17 and, therefore, designated as Th17 cells. Several studies support a pivotal role for serum cytokines in the pathogenesis of ITP and provide evidence to suggest that helper Tlymphocytes polarize into Th1 and Th2 immune response. we aimed to investigate the role of T helper17 cells and interleukin-17 in the pathogenesis of ITP in Egyptian children.

GL7 ligand expression defines a novel subset of CD4+ TRM cells in lungs recovered from pneumococcus

Streptococcus pneumoniae is the most common etiology of bacterial pneumonia, one of the leading causes of death in children and the elderly worldwide. During non-lethal infections with S. pneumoniae, lymphocytes accumulate in the lungs and protect against reinfection with serotype-mismatched strains. Cluster of differentiation CD4+ resident memory T (TRM) cells are known to be crucial for this protection, but the diversity of lung CD4+ TRM cells has yet to be fully delineated. We aimed to identify unique subsets and their contributions to lung immunity. After recovery from pneumococcal infections, we identified a distinct subset of CD4+ T cells defined by the phenotype CD11ahiCD69+GL7+ in mouse lungs. Phenotypic analyses for markers of lymphocyte memory and residence demonstrated that GL7+ T cells are a subset of CD4+ TRM cells. Functional studies revealed that unlike GL7- TRM subsets that were mostly (RAR-related Orphan Receptor gamma T) RORγT+, GL7+ TRM cells exhibited higher levels of (T-box expressed in T cells) T-bet and Gata-3, corresponding with increased synthesis of interferon-γ, interleukin-13, and interleukin-5, inherent to both T helper 1 (TH1) and TH2 functions. Thus, we propose that these cells provide novel contributions during pneumococcal pneumonia, serving as important determinants of lung immunity.

Th22 cells and the intestinal mucosal barrier.

T-helper 22 (Th22) cells represent a novel subset of CD4+ T cells that exhibit distinctive characteristics, namely the secretion of IL-22 while abstaining from secreting IL-17 and interferon-γ (IFN-γ). These cells serve as the primary source of IL-22, and both Th22 cells and IL-22 are believed to play a role in maintaining intestinal mucosal homeostasis in inflammatory bowel disease (IBD). However, the precise functions of Th22 cells and IL-22 in this context remain a subject of debate. In this work, we aimed to elucidate their impact on the integrity of the intestinal mucosal barrier by presenting an overview of the molecular structure characteristics and functional effects of Th22 cells and IL-22. Furthermore, we would explore targeted treatment approaches and potential therapeutic strategies focusing on the Th22 and IL-22 pathways.

The Role of T Follicular Helper Cells and Interleukin-21 in the Pathogenesis of Inflammatory Bowel Disease.

T follicular helper (Tfh) cells represent a novel subset of CD4+ T cells which can provide critical help for germinal center (GC) formation and antibody production. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), programmed death 1 (PD-1), inducible costimulatory molecule (ICOS), B cell lymphoma 6 (BCL-6), and the secretion of interleukin-21 (IL-21). Given the important role of Tfh cells in B cell activation and high-affinity antibody production, Tfh cells are involved in the pathogenesis of many human diseases. Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases characterized by symptoms such as diarrhea, abdominal pain, and weight loss. Ulcerative colitis (UC) and Crohn's disease (CD) are the most studied types of IBD. Dysregulated mucosal immune response plays an important role in the pathogenesis of IBD. In recent years, many studies have identified the critical role of Tfh cells and IL-21 in the pathogenic process IBD. In this paper, we will discuss the role of Tfh cells and IL-21 in IBD pathogenesis.

Role of Th22 Cells in Human Viral Diseases.

Naive CD4+ T cells can differentiate into different cell subsets after receiving antigen stimulation, which secrete corresponding characteristic cytokines and thereby exert biological effects in various diseases. Th22 cells, a novel subset of CD4+ T cells, are different from Th1, Th2, Th17, and Treg cell subsets, which have been discovered in recent years. They can express CCR4, CCR6, and CCR10 molecules and secrete IL-22, IL-13, and TNF-α. They are not able to secrete IL-17, IL-4, and interferon-γ (IFN-γ). IL-22 is considered as a major effector molecule of Th22 cells whose functions and mechanisms of regulating cell differentiation have been constantly improved. In this review, we provide an overview of the origin, differentiation of Th22 cells. Moreover, we also describe the interrelationships between Th22 cells and Th17, Th1, and Th2 cells. Additionally, the role of Th22 cells were discussed in human diseases with virus infection, which will provide novel insight for the prevention and treatment of viral infection in human.

Cutaneous T cells promote distinct cellular outcomes in human keratinocytes and fibroblasts

Abstract Human skin is a barrier tissue home to a highly specialized immune environment in which leukocytes coordinate with local epithelial and stromal tissue in response to physical, chemical, and biological stresses. T cells are abundant in the skin and are required for both host defense to pathogens and the subsequent repair of damaged tissue. Cutaneous lymphocytes include both resident and migratory fractions, which can be identified and isolated using expression of the cutaneous lymphocyte antigen (CLA). There are multiple subsets of CLA+ T cells, each having a distinct phenotype and functional capacity, however their precise roles in contributing to host-protective and tissue-repair responses remains incompletely understood. We assessed the function of eight different CD4+CLA+ cutaneous T cell subsets from the skin and blood, including traditional T helper lineages and a novel subset of CD4+CLA+CD103+ T cells with a tissue repair phenotype, by bulk RNAseq analysis of keratinocytes and fibroblasts following administration of activated T cell supernatants. Differential gene expression and pathway analysis reveal distinct cellular outcomes in keratinocytes and fibroblasts that depend strongly on T cell source and the activity of specific cytokines. Our findings define a diverse array of immune-induced states in the skin that are dependent on the unique functional capacity of various T cell subsets, thereby constructing a comprehensive tool to map how cutaneous T cells contribute to pathological disruption, tissue repair and return to homeostasis within human skin.

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.

Decreased circulating Th22 and Th17 cells in patients with aplastic anemia

BackgroundAplastic anemia (AA) is an immune-mediated disorder and mainly related to active destruction of hematopoietic cells by effector T lymphocytes. T helper (Th) 22 cells characterized as a novel subset of CD4+ T cells participate in the pathogenesis of autoimmune and hematological diseases. However, the role of Th22 subset in AA remains unknown. Methods31 untreated AA patients and 30 healthy controls were included in this study. The percentages of Th22, Th17 and pure Th17 cells in peripheral blood were detected by flow cytometry. ELISA to measure interleukin (IL)-22 and IL-17A plasma levels and qRT-PCR for the mRNA levels of Th22 and Th17 related molecules were performed. ResultsThe proportions of Th22, pure Th17, Th17 cells and plasma levels of IL-22 were significantly lower in untreated AA patients than those in normal controls. A positive correlation was found between Th22 and pure Th17 cells in AA. Moreover, percentages of Th22 cells correlated positively with reticulocyte counts and percentages. In addition, STAT3/STAT5 mRNA expression ratio was elevated in AA patients. ConclusionTogether, our results showed Th22 cells correlating with clinical characteristics of AA patients, indicating a possible role of Th22 immune response in the pathogenesis and therapeutic intervention of AA.

Peripheral blood Th9 cells and eosinophil apoptosis in asthma patients

Background and objectiveTh9 cells producing interleukin (IL) 9 are novel subset of CD4+ T helper cells, which might contribute to airway inflammation in asthma. Moreover, the effect of IL-9 on eosinophils is still not fully understood. Study aim was to evaluate peripheral blood Th9 cells and eosinophil apoptosis in allergic asthma patients. Materials and methodsEighteen patients with allergic asthma and fourteen patients with allergic rhinitis were examined. Control group included sixteen healthy subjects. Allergic asthma and rhinitis patients did not use corticosteroids and antihistamines at least for 1 week. Peripheral blood eosinophils and CD4+ cells were isolated by high density gradient centrifugation and magnetic separation. Th9 cells and apoptotic eosinophils were estimated by flow cytometer. Serum IL-9 and IL-5 concentration were determined by ELISA. ResultsPeripheral blood Th9 cells percentage was increased in allergic asthma group compared with allergic rhinitis and control group (0.74%±0.32% vs. 0.19%±0.10% and 0.15%±0.08%, respectively, P<0.05). The same tendency was observed for IL-9 (P<0.01). Percentage of peripheral blood apoptotic eosinophils was decreased in allergic asthma and allergic rhinitis groups compared with control group (P<0.05). IL-9 concentration correlated with percentage of Th9 cells (r=0.64, P<0.05) and negatively with percentage of apoptotic eosinophils in allergic asthma group (r=−0.58, P<0.05). Negative correlation was found between apoptotic eosinophils count and IL-5 concentration in allergic asthma group (r=−0.76, P<0.05). ConclusionsPatients with allergic asthma demonstrate increased peripheral blood Th9 cells count and serum IL-9, while eosinophil apoptosis is inversely related to IL-9 concentration.

T helper cell 17 (Th17) and its role in solid organ transplantation

T helper 17 cells (Th17) are a novel subset of CD4+ T cells that undergo differentiation from naive CD4 T cells through the activation of a key nuclear transcription factor,retinoic-acid-receptor-related orphan receptor γt (RORγt),and in the presence of multiple cytokines,such as transforming growth factorβ1 (TGF-β1),interleukin6 (IL-6),as well as IL-23.Th17 cells induce their biological effect by secreting IL-17A and other cytokines.Research has demonstrated that Th17 cells have an intimate relationship with acute/chronic transplant reactions and that Th17 cell lineages have the possibility to become the new target for treating transplant rejections.Identification of Th17 cells also provides an additional strategy for inducing immune tolerance. Key words: T helper cell 17; Rejection; Immune tolerance

Involvement of Th17 cells in patients of urothelial carcinoma of bladder

Bladder cancer is the second most common urologic malignancy after prostate with urothelial carcinoma accounting for 90% of all bladder cancers. Th17 cells representing novel subset of CD4(+) cells have well described roles in autoimmune diseases and inflammation. Recent studies suggest a potential impact of Th17 cells in tumor immunology. The implication of Th17 cells in bladder cancer can be judged by the expression of their related cytokines and a key transcription factor, RORγt which helps in the development of Th17 cells. Therefore, we aim to assess expression of Th17 related cytokines, RORγt and distribution of Th17 cells to understand its involvement in bladder cancer. In our study, frequency of Th17 cells was significantly higher (p-value <0.001) in patients than controls. Circulating levels of pro-inflammatory cytokines IL-17A, IL-23 and IL-6 were also significantly elevated in patients. Relative mRNA expression of IL-17A and RORγt in PBMCs and fold change in gene expression in tissues was found to be significantly elevated. These findings indicate the possible involvement of Th17 cells in urothelial carcinoma of bladder. Further the data can be validated to better understand the role of Th17 cells in this disease which might help in formulating targeted therapeutic strategy in future.

T follicular helper cells and some skin diseases

T follicular helper (Tfh) cells are a novel subset of CD4+ T cells that provide helper functions to B cells in humoral immune response.They may migrate into germinal center (GC) to stimulate B cells to produce antibodies under the effect of some molecules expressed by themselves,such as CXC chemokine receptor 5 (CXCR5),inducible T-cell co-stimulator (ICOS),B cell lymphoma-6 (bcl-6),interleukin (IL)-21,and so on.Currently,Tfh cells are considered to be the major cell helping B cells.Recent studies have shownthat Tfh cells are of great significance to the development,treatment and prognosis of some skin disorders. Key words: T-lymphocytes, helper-inducer; Skin diseases

Th17 (IFNγ- IL17+) CD4+ T Cells Generated After Burn Injury May Be a Novel Cellular Mechanism for Postburn Immunosuppression

The mechanism responsible for initiating and controlling the immunosuppressive response after burn injury remains unknown. Interleukin-17 (IL-17) secreting Th17 (interferon [IFN]γ IL17) cells are a novel subset of CD4 T cells associated with a weak, proinflammatory response that antagonizes the proinflammatory Th1 (IFNγ IL17) response. Given that transforming growth factor-β and IL6 mediate Th17 cell development, we hypothesized that burn injury may generate Th17 cells that could mediate postburn immunosuppression. After a 20% total body surface area burn in female C57BL/6 mice, wound-draining lymph nodes were harvested 3 days, 7 days, or 14 days after injury. CD4 T cells were enriched by magnetic selection, and flow cytometry was used to identify intracellular IL17 and IFNγ in CD3CD4 T cells. Additional purified CD3CD4 T cells were cultured with Th17 polarizing IL6 and transforming growth factor-β for 4 days, and flow cytometry was again used to identify intracellular IL17 and IFNγ in CD4 T cells. The number and percentage of preformed Th17 cells was significantly greater in burn mice compared with sham at all time points. In addition, the ratio of Th17 cells to Th1 cells was always significantly higher in burn mice compared with sham. These differences were eliminated in Th17 polarizing conditions in vitro. CD4 T cells never generated both IL17 and IFNγ. These results demonstrate for the first time that Th17 cells (IFNγ IL17) are spontaneously generated after burn injury. Given that Th17 cells (IFNγ IL17) are antagonistic to Th1 (IFNγ IL17) cells, these results suggest a novel mechanism for initiating and controlling postburn immunosuppression that deserves further investigation.

Induction of a Th17 cell response by Helicobacter pylori Urease subunit B

Th17 cells represent a novel subset of CD4 + T cells, which is associated with Helicobacter pylori infection. In the present study, we investigated the potential role of Urease subunit B (UreB) in the induction of Th17 cell response. Co-cultured splenic lymphocytes from H. pylori-infected mice with the recombinant UreB (rUreB) elevated IL-17 secretion and caused an increase in the number of Th17 cells. The expression of IL-6 and IL-23 p19 was significantly increased in rUreB-stimulated macrophages. Whole cell protein (WCP) of UreB-deficient strain (UreB − strain) induced less Th17 cell responses than that of wild-type strain. In addition, subcutaneous and intranasal immunization of rUreB elicited antigen-specific Th17 cell responses. Intranasal immunization of rUreB reduced H. pylori colonization in the stomach, which was closely related with the increased rUreB-specific Th17 cell responses. These results suggest that UreB is an important protein which is able to elicit Th17 cell responses against H. pylori both in vivo and in vitro.

A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma

The inflammatory cytokine interleukin (IL)-17 is involved in the pathogenesis of allergic diseases. However, the identity and functions of IL-17-producing T cells during the pathogenesis of allergic diseases remain unclear. Here, we report a novel subset of T(H)2 memory/effector cells that coexpress the transcription factors GATA3 and RORγt and coproduce T(H)17 and T(H)2 cytokines. Classical T(H)2 memory/effector cells had the potential to produce IL-17 after stimulation with proinflammatory cytokines IL-1β, IL-6, and IL-21. The number of IL-17-T(H)2 cells was significantly increased in blood of patients with atopic asthma. In a mouse model of allergic lung diseases, IL-17-producing CD4(+) T(H)2 cells were induced in the inflamed lung and persisted as the dominant IL-17-producing T cell population during the chronic stage of asthma. Treating cultured bronchial epithelial cells with IL-17 plus T(H)2 cytokines induced strong up-regulation of chemokine eotaxin-3, Il8, Mip1b, and Groa gene expression. Compared with classical T(H)17 and T(H)2 cells, antigen-specific IL-17-producing T(H)2 cells induced a profound influx of heterogeneous inflammatory leukocytes and exacerbated asthma. Our findings highlight the plasticity of T(H)2 memory cells and suggest that IL-17-producing T(H)2 cells may represent the key pathogenic T(H)2 cells promoting the exacerbation of allergic asthma.

Helicobacter pylori-infected macrophages induce Th17 cell differentiation

Th17 cells represent a novel subset of CD4 + T cells, which is associated with chronic inflammation. The present study evaluated Th17 cell responses to Helicobacter pylori infection in mouse model and CD4 + T cell differentiation in response to H. pylori-infected macrophages. Th17 cells were observed in the H. pylori-infected gastric tissue. Co-culture of CD4 + T cells with H. pylori-infected macrophages elevated IL-17 and IFN-γ secretion, up-regulated retinoid-related orphan receptor gamma t (RORγt) and T box expressed in T cells (T-bet) expression and increased the numbers of Th17 and Th1 cells. The expression of CD40, CD80, and CD86 and the secretion of IL-6, TGF-β1, IL-23, and CCL20 were significantly increased in H. pylori-stimulated macrophages. NF-κB pathway participated in the production of IL-6, IL-23, and CCL20 from macrophages in response to H. pylori, and inhibition of NF-κB pathway of macrophages resulted in less Th17 cell differentiation. Taken together, these results suggest that H. pylori induces Th17 cell differentiation via infected macrophages.

Association between polymorphisms in interleukin‐17A and interleukin‐17F genes and risks of gastric cancer

Chronic inflammation is the hallmark of the pathogenesis of Helicobacter pylori-induced gastric cancer. Interleukin (IL)-17A and IL-17F are inflammatory cytokines expressed by a novel subset of CD4+ Th cells and play critical function in inflammation and probably in cancer. We conducted a case-control study including 1,010 gastric cancer patients and 800 healthy controls to assess the association between IL-17A G197A and IL-17F A7488G polymorphisms and risk of gastric cancer. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Logistic regression and Cox-proportional hazards analyses were used to evaluate the associations between polymorphisms and gastric cancer susceptibility, clinicopathological features and survival. After adjusted for age and gender, IL-17F 7488GA and GG genotypes were associated with an increased risk of gastric cancer compared with AA genotype [OR 1.51, 95% confidence interval (CI): 1.22-1.87 for GA; OR 1.61, 95% CI: 1.03-2.51 for GG]. Further stratification analyses indicated that the effect of IL-17F 7488GA genotype was noteworthy in gastric cancer patients of noncardia, intestinal type, poorly and moderately differentiated, age older than 40, large tumor size and lymph node metastasis. IL-17A 197AG genotype was associated with increased risk of poorly differentiated, TNM I/II, age of 40-65-year subtypes of gastric cancer, but not with total gastric cancer risk (p = 0.098). No significant relationship was observed between polymorphisms and survival of gastric cancer patients. These findings suggest that polymorphism of IL-17F 7488 involved in susceptibility to gastric cancer, which also influenced certain subtypes according to clinicopathological features, whereas IL-17A 197 may be less relevant.

Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia

T helper type 17 (Th17) cells, which represent a novel subset of CD4(+) T cells, play an active role in inflammatory and autoimmune diseases. Recent studies have also suggested that they have an impact on solid tumours. However, the nature of Th17 cells in haematological malignancies remains unknown. In this study, we investigated Th17 cell frequency and secretion of related cytokines in patients with acute myeloid leukaemia (AML). First, we found that Th17 cell frequencies were increased significantly in peripheral blood samples from untreated patients with AML, compared with those from healthy volunteers. Moreover, increased interleukin (IL)-17 concentrations accompanied the increased Th17 cell frequencies in these patients. These results suggest that Th17 cells may play a role in the pathogenesis of AML. Secondly, we found that the increased Th17 cell frequencies were reduced when patients achieved complete remission after chemotherapy, suggesting that measurement of Th17 cell frequencies may have clinical value in the evaluation of therapeutic effect. In addition, we found that IL-6 and transforming growth factor (TGF)-beta1 concentrations increased in the untreated patients and that IL-6 concentrations showed a positive correlation with the frequencies of Th17 cells, suggesting that IL-6 may play an important role in Th17 cell differentiation in patients with AML.

Differentiation and function of pro-inflammatory Th17 cells

After activation, CD4+ helper T (Th) cells differentiate into cytokine-secreting effector subsets. A novel subset of CD4+ helper T (Th) cells that produce two related cytokines IL-17 and IL-17F has been recently identified and shown to play critical function in inflammation and autoimmunity. Here I summarize recent work by us as well as other investigators in understanding the transcriptional regulation of Th17-cell differentiation, their developmental relationship with regulatory T cells and the function of IL-17 and IL-17F in vivo.

Regulation and pro‐inflammatory function of interleukin‐17 family cytokines

The interleukin-17 (IL-17) family consists of six cytokines in mammals. Among them, IL-17 and IL-17F are expressed by a novel subset of CD4(+) helper T cells and play critical function in inflammation and autoimmunity. IL-17E, also called IL-25, has been associated with allergic responses. Here, I summarize recent work by my laboratory as well as other investigators in understanding the regulation and function of these three cytokines. From these studies, IL-17 family cytokines may serve as novel targets for pharmaceutical intervention of immune and inflammatory diseases.