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Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin condition characterized by a multifaceted pathophysiology that gives rise to diverse clinical manifestations. The management of AD remains challenging due to the suboptimal efficacy of existing treatment options. Nonetheless, recent progress in elucidating the underlying mechanisms of the disease has facilitated the identification of new potential therapeutic targets and promising drug candidates. In this review, we summarize the newest data, considering multiple connections between IL-22 and AD. The presence of circulating IL-22 has been found to correlate with the severity of AD and is identified as a critical factor driving the inflammatory response associated with the condition. Elevated levels of IL-22 in patients with AD are correlated with increased proliferation of keratinocytes, alterations in the skin microbiota, and impaired epidermal barrier function. Collectively, these factors contribute to the manifestation of the characteristic symptoms observed in AD. [ABSTRACT FROM AUTHOR]

The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.

Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin condition characterized by a multifaceted pathophysiology that gives rise to diverse clinical manifestations. The management of AD remains challenging due to the suboptimal efficacy of existing treatment options. Nonetheless, recent progress in elucidating the underlying mechanisms of the disease has facilitated the identification of new potential therapeutic targets and promising drug candidates. In this review, we summarize the newest data, considering multiple connections between IL-22 and AD. The presence of circulating IL-22 has been found to correlate with the severity of AD and is identified as a critical factor driving the inflammatory response associated with the condition. Elevated levels of IL-22 in patients with AD are correlated with increased proliferation of keratinocytes, alterations in the skin microbiota, and impaired epidermal barrier function. Collectively, these factors contribute to the manifestation of the characteristic symptoms observed in AD.

Abstract 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.

ABSTRACTMetastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Objective: To investigate the expression and clinical significance of helper T (Th) 22 cell and its cytokines in patients with diffuse large B-cell lymphoma (DLBCL) . Methods: 121 patients with DLBCL (DLBCL group) and 70 healthy volunteers (control group) who were admitted to the First Affiliated Hospital of Hebei North University from June 2019 to June 2021 were selected. The percentage of Th22 cell and the levels of cytokines-interleukin (IL-22), IL-13, IL-6 and tumor necrosis factor (TNF) -α in peripheral blood before and after treatment were detected. The difference of levels of the percentage of Th22 and serum IL-22, IL-13, IL-6 and TNF-αwere compared between DLBCL group and control group, different AnnArbor clinical stages, International Prognosis Index (IPI) score and Hans immune classification and different efficacy of patients with DLBCL. Results: The percentage of Th22 cell in peripheral blood and the levels of serum of IL-22, IL-13, IL-6 and TNF-α in the DLBCL group were higher than those in the control group (P＜0.05) . The percentage of Th22 cell in peripheral blood, the levels of serum IL-22, IL-13, IL-6 and TNF-α in the stage Ⅲ～Ⅳ group, high-medium risk group and high risk group, and non-GCB group before treatment were higher than those in the stage I～ Ⅱ group, low risk group and low-medium risk group and GCB group, respectively (all P＜0.05) . 39 of 121 patients were judged to be non-responders to treatment,and the patients were divided into the ineffective group (n=39) and effective group (n=82) based on efficacy. The percentage of Th22 cell in peripheral blood and the levels of serum IL-22, IL-13, IL-6 and TNF-α in the ineffective group after treatment had no significant changes compared with those before treatment (P＞0.05), and the ineffective group before and after treatment were higher than the effective group (P＜0.05) . Conclusion: The percentage of Th22 in peripheral blood and the levels of serum IL-22, IL-13, IL-6 and TNF-α in patients with DLBCL increased, which are associated with high AnnArbor clinical stages, high IPI score, non-GCB type and poor clinical treatment effect. The clinic can adjust the treatment regimen by monitoring the levels of the above indicators and improve the effective rate of treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Psoriasis and hidradenitis suppurativa are chronic inflammatory skin diseases that can develop together, negatively impacting on the patient’s quality of life. We aimed to review the most up-to-date information regarding the epidemiology, pathogenesis, clinical presentation and possible therapeutical choices in patients with both psoriasis and hidradenitis suppurativa, thus linking these two autoimmune and autoinflammatory conditions. A narrative review of articles dating from 2017 to 2022 has been performed using the PubMed database. We analyzed the case reports and case series found in the literature regarding patients who suffered from both psoriasis and HS. Psoriasis arose before hidradenitis suppurativa in the majority of cases, while only a minority of them had hidradenitis suppurativa before psoriasis. Interestingly, some patients suffered from paradoxical hidradenitis suppurativa following biological therapy administered to treat the already present psoriasis. Lastly, new biological drugs have been marketed with great success for the outcome of psoriasis, but similar progress did not happen for hidradenitis. Novel therapeutic approaches and lines of research are needed for the treatment of these pathologies, even if concomitant, in order to improve patient’s quality of life.

A synthetic progestin, medroxyprogesterone acetate (MPA), was used in a novel study to determine progestin effects on human purified macrophages and Th1, Th2, Th17, Th22 cells. MPA concentrations were equivalent to those in the serum of women after 6 and 9 months of progestin use. MPA has no effect on the proliferation of PBMCs and CD4+ T cell clones induced by immobilized anti-CD3 antibodies or by antigen (streptokinase). However, MPA decreases production and mRNA expression of IL-5, IL-13, IFN-γ, T-bet, RORC, and IL-17A but increases production and mRNA expression of IL-22 by CD4+ Th22 cell clones and decreases IL-22 production by Th17 cells. MPA inhibits RORC, but not T-bet and AHR, by Th17 cells but increases AHR mRNA and T-bet expression of established CD4+ Th22 cell clones. This suggests that MPA, at concentrations equivalent to those found in the serum of women after treatment for contraception and hormone replacement therapy, can directly inhibit Th1 responses (against intracellular bacteria and viruses), Th17 (against extracellular bacteria and fungi), Th2 (against parasites) but MPA therapy increases IL-22 produced by Th22 cells mediated by an increased expression of AHR and T-bet controlling inflammation. MPA could be responsible for the tissue damage limited by IL-22 in absence of IL-17A.

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) still poses a major challenge for curative treatment. Although some new therapeutic options arose during the last decade, the overall prognosis remains poor. New therapies might include the modification of tumor-promoting or -inhibiting mediators of the immune system, such as interleukin (IL)-22 and its natural antagonist IL-22 binding protein (IL-22BP). Thus, this study aimed to investigate the role and underlying mechanisms of IL-22 and IL-22BP signaling in liver cancer. Using two different mouse models, we found that IL-22 promoted HCC development, while IL-22BP led to reduced tumor growth. IL-22 was mainly produced by a subset of T cells in HCC, whereas IL-22BP was abundantly secreted by neutrophils. Importantly, we identified hepatocytes as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes reduced STEAP4 expression-a known oncogene-in an HCC mouse model in vivo, and STEAP4 expression correlated with IL22 levels in human HCC samples. Taken together, these data might pave the way for new therapeutical approaches by blocking IL-22 or its downstream signaling in HCC. Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22–IL-22BP axis in HCC. [ABSTRACT FROM AUTHOR]

Although atopic dermatitis (AD) is primarily a Th2-driven disease, it shows high heterogeneity with additional variable contributions of the Th22, Th17, and Th1 pathways, depending on the subtype of the disease. Expanding knowledge and understanding of AD pathogenesis has promoted the development of numerous novel therapeutics that target cytokines and their signaling molecules, representatively, Janus kinases, involved in the underlying immune pathways, resulting in therapeutic success and failure. The first FDA approval was for the targeted biologic dupilumab. Although this proved the therapeutic relevance of targeting Th2 cytokines in moderate-to-severe forms of AD, it did not treat all patients, necessitating additional targeted therapeutics that modulate other cytokine pathways to resolve AD in all subtypes. Three more recently FDA-approved targeted therapeutics and several others that have been developed represent different targeted approaches directed to the Th2, Th22, Th17, or Th1 pathways. This review summarizes the main features and clinical outcomes of various approaches targeting cytokines and signaling molecules in these different pathways in view of both successful and failed cases, with a discussion of their therapeutic implications. In future, AD should be treated with more specific treatments reflecting the disease heterogeneity, but the current development of targeted therapeutics has faced some challenges in this context, which is also discussed. [ABSTRACT FROM AUTHOR]

Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization., Competing Interests: Competing interests The authors declare no competing interests.

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. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has clinical manifestations ranging from mild symptoms to respiratory failure, septic shock, and multi-organ failure. Lymphocytes are divided into different subtypes based on their cytokine production pattern. In this study, we investigated the role of cytokine expressions of CD4+ T (T helper [Th]1, Th2, Th17, Th22) and CD8+ T cell subtypes (T cytotoxic [Tc]1, Tc2, Tc17, Tc22) in the pathogenesis of COVID-19. Peripheral blood mononuclear cells (PBMCs) were extracted with Ficoll by density gradient centrifugation from blood samples of 180 COVID-19 patients (children and adults) and 30 healthy controls. PBMCs were stimulated with PMA and Ionomycin and treated with Brefeldin A in the fourth hour, and a 10-colored monoclonal antibody panel was evaluated at the end of the sixth hour using flow cytometry. According to our findings, the numbers of Th22 (CD3+, CD4+, and interleukin [IL]-22+) and Tc22 (CD3+, CD8+, IL-22+) cells increased in adult patients regardless of the level of pneumonia (mild, severe, or symptom-free) as compared with healthy controls (p < 0.05). In addition, the number of Tc17 (CD3+, CD8+, and IL-17A+) cells increased in low pneumonia and severe pneumonia groups compared with the healthy controls (p < 0.05). Both IL-22 and IL-17A production decreased during a follow-up within 6 weeks of discharge. Our findings suggest that the increase in only IL-22 expressed Tc22 cells in the 0–12 age group with a general symptom-free course and higher levels of Th22 and Tc22 in uncomplicated adult cases may indicate the protective effect of IL-22. On the contrary, the association between the severity of pneumonia and the elevation of Tc17 cells in adults may reveal the damaging effect of IL-22 when it is co-expressed with IL-17. [ABSTRACT FROM AUTHOR]

T helper cell 22 are abundant in Hepatitis B Virus-related hepatocellular carcinoma tissue, and the main cytokine interleukin 22 produced by Th22 cells is closely related to the initiation and development of HCC. Understanding the role of Th22/IL-22 in the progression of HBV-related HCC will facilitate new therapeutic development. Th22 cells were isolated from peripheral blood of healthy donors and co-cultured with HBV positive HepG2.2.15 cells. IL-22 secretion and HepG2.2.15 cell proliferation and apoptosis were monitored. Expressions of p-STAT3, Cyclin D1, Bcl-2, and cleaved caspase 3 were detected by Western blot analysis. Th22 cells significantly promoted the proliferation and inhibited the apoptosis of HepG2.2.15 cells; up-regulated expression of p-STAT3, Cyclin D1 and Bcl-2, and down-regulated cleaved caspase 3 in HepG2.2.15 cells. These effects were significantly attenuated when IL-22 and STAT3 was knockdown in Th22 and HepG2.2.15 cells, respectively. Our data suggests that HBV induces host Th22 cells to overexpress IL-22, which in turn triggers over-activation of STAT3 and its downstream signaling proteins to promote HCC progression. [ABSTRACT FROM AUTHOR]

Abstract 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.

Increasing rates of life-threatening infections and decreasing susceptibility to antibiotics urge development of an effective vaccine targeting Staphylococcus aureus. This study evaluated the efficacy and immunologic mechanisms of a vaccine containing a recombinant glycoprotein antigen (NDV-3) in mouse skin and skin structure infection (SSSI) due to methicillin-resistant S. aureus (MRSA). Compared with adjuvant alone, NDV-3 reduced abscess progression, severity, and MRSA density in skin, as well as hematogenous dissemination to kidney. NDV-3 induced increases in CD3+ T-cell and neutrophil infiltration and IL-17A, IL-22, and host defense peptide expression in local settings of SSSI abscesses. Vaccine induction of IL-22 was necessary for protective mitigation of cutaneous infection. By comparison, protection against hematogenous dissemination required the induction of IL-17A and IL-22 by NDV-3. These findings demonstrate that NDV-3 protective efficacy against MRSA in SSSI involves a robust and complementary response integrating innate and adaptive immune mechanisms. These results support further evaluation of the NDV-3 vaccine to address disease due to S. aureus in humans.

Increasing rates of life-threatening infections and decreasing susceptibility to antibiotics urge development of an effective vaccine targeting Staphylococcus aureus. This study evaluated the efficacy and immunologic mechanisms of a vaccine containing a recombinant glycoprotein antigen (NDV-3) in mouse skin and skin structure infection (SSSI) due to methicillin-resistant S. aureus (MRSA). Compared with adjuvant alone, NDV-3 reduced abscess progression, severity, and MRSA density in skin, as well as hematogenous dissemination to kidney. NDV-3 induced increases in CD3+ T-cell and neutrophil infiltration and IL-17A, IL-22, and host defense peptide expression in local settings of SSSI abscesses. Vaccine induction of IL-22 was necessary for protective mitigation of cutaneous infection. By comparison, protection against hematogenous dissemination required the induction of IL-17A and IL-22 by NDV-3. These findings demonstrate that NDV-3 protective efficacy against MRSA in SSSI involves a robust and complementary response integrating innate and adaptive immune mechanisms. These results support further evaluation of the NDV-3 vaccine to address disease due to S. aureus in humans.

Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking. We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls. We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry. T H 2/T H 22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. T H 17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. T H 1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with T H 2/T H 22-related markers in all pediatric age groups. The shared signature of AD across ages is T H 2/T H 22-skewed, yet differential expression of specific T H 2/T H 22-related genes, other T H pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints. [ABSTRACT FROM AUTHOR]

Neutrophil-derived bactericidal/permeability-increasing protein (BPI) is known for its bactericidal activity against gram-negative bacteria and neutralization of lipopolysaccharide. Here, we define BPI as a potent activator of murine dendritic cells (DCs). As shown in GM-CSF-cultured, bone-marrow-derived cells (BMDCs), BPI induces a distinct stimulation profile including IL-2, IL-6, and tumor necrosis factor expression. Conventional DCs also respond to BPI, while M-CSF-cultivated or peritoneal lavage macrophages do not. Subsequent to BPI stimulation of BMDCs, CD4+ T cells predominantly secrete IL-22 and, when naive, preferentially differentiate into T helper 22 (Th22) cells. Congruent with the tissue-protective properties of IL-22 and along with impaired IL-22 induction, disease severity is significantly increased during dextran sodium sulfate-induced colitis in BPI-deficient mice. Importantly, physiological diversification of intestinal microbiota fosters BPI-dependent IL-22 induction in CD4+ T cells derived from mesenteric lymph nodes. In conclusion, BPI is a potent activator of DCs and consecutive Th22 cell differentiation with substantial relevance in intestinal homeostasis. [Display omitted] • Bactericidal/permeability-increasing protein (BPI) is an activator of dendritic cells (DCs) • BPI-dependent DC activation mediates differentiation of naive CD4+ T cells into Th22 cells • Bpi −/− mice exhibit reduced IL-22 induction and increased disease severity during colitis • Microbiota diversification fosters BPI-dependent activation of IL-22-positive CD4+ T cells Bülow et al. show that bactericidal/permeability-increasing protein (BPI) has substantial relevance in intestinal homeostasis. Following activation of murine dendritic cells by BPI, CD4+ T cells predominantly differentiate into IL-22-secreting Th22 cells. This BPI-DC-IL-22 axis is fostered by diversification of intestinal microbiota and improves the outcome of dextran sodium sulfate-induced colitis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yamamura, Nakashima and Otsuka.)

Xingfen Su,1 Handong Wang,2 Yuanxiang Lin,1 Fuxiang Chen1 1Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, People’s Republic of China; 2Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, People’s Republic of China Background: Intracerebral hemorrhage (ICH) is a devastating neurological injury associated with significant mortality. Necroptosis is a newly identified type of programmed necrosis initiated by the activation of tumor necrosis factor alpha. Evidences had demonstrated the importance of necroptosis in neuronal cell death. Necrostatin-1 is a specific inhibitor of necroptosis. The present study was carried out to explore whether RIP1/RIP3 pathways participate in hemin induced cell death in HT-22 hippocampal neuronal cells and investigate the potential neuroprotection of necrostatin-1 in hemin induced cell death in HT-22. Methods: First, different concentrations of hemin (0, 25, 50, 100 µmol/L) were added to HT-22 cells. Propidium iodide (PI) positive cells and cell viability were measured at 24 hours after hemin treatment. Then, necrostatin-1, pan-caspase inhibitor Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk) and reactive oxygen species (ROS) scavenger butylated hydroxyanisole (BHA) were applied to hemin-treated HT-22 cells. PI positive cells and cell viability were measured at 24 hours after hemin treatment. MitoSox Red was used to indicate ROS level. Last, the effect of RIP3 in hemin induced HT-22 cell death was explored through RIP3 knockdown using siRNA. PI positive cells, cell viability and ROS lever were measured at 24 h after hemin treatment. Results: Hemin could induce a dose dependent cell death in HT22 neural cells. RIP1 specific inhibitor necrostatin-1 significantly inhibited cell death induced by hemin in HT-22 cells, greatly reducing PI positive cells, dramatically improving cell viability and decreasing ROS accumulation. BHA could significantly inhibit PI positive cells induced by hemin in HT-22 cells. Furthermore, silencing of RIP3 using siRNA attenuated hemin induced cell death in HT-22 cells, greatly reducing PI positive cells, dramatically improving cell viability and decreasing ROS accumulation. Conclusion: These data revealed that RIP1/RIP3 might mediate hemin induced cell death in HT-22 cells, and necrostatin-1 played a neuroprotection role in hemin induced cell death in HT-22. RIP1 and RIP3 might represent novel therapeutic targets for ICH. Keywords: intracerebral hemorrhage, necroptosis, HT22, RIP1, RIP3, necrostatin-1

Background: This study aimed to investigate the expression of Th9 and Th22 cells in rats with cerebral palsy (CP) after human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation. Methods: First, hUC-MSCs were isolated from fresh umbilical cords and identified. Rats were divided into the normal group, CP group, and hUC-MSC transplantation group. The Morris water maze and balance beam tests were performed to evaluate the neurobehavioral ability of the rats. The levels of TNF-α, IL-6, IL-9, and IL-22 in rat brain tissues were detected by ELISA. Th9 and Th22 proportions in brain tissues were detected by flow cytometric analysis. The mRNA levels of IL-9, IL-22, PU.1, and AHR in brain tissues were determined by qRT-PCR. Results: hUC-MSC transplantation enhanced the neurobehavioral ability of CP rats. Furthermore, Th9 and Th22 proportions were decreased in brain tissues from CP rats after hUC-MSC transplantation. The levels of proinflammatory cytokines (TNF-α and IL-6), Th9-related IL-9 and PU.1, and Th22-related IL-22 and AHR were markedly higher in brain tissues from CP rats than in brain tissues from control rats, but their levels were significantly decreased after hUC-MSC transplantation. Conclusion: Our data indicate that Th9 and Th22 proportions are decreased in CP rats after hUC-MSC transplantation. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) has been shown to be one of the leading causes of peptic ulcer diseases (PUDs) and gastritis. T helper-22 (Th22) cells and its most important cytokine, interleukin-22 (IL-22) are importantly active in inflammation and inflammatory tissues. Since inflammation is one of the main attributes of infection caused by H. pylori and resulting complications (gastritis and gastrointestinal ulcer), this study was designed to evaluate the Th22 cells count and the IL-22 protein expression in people suffering from PUD and gastritis. The present study was conducted on 55 patients with gastritis, 47 patients with PUD and 48 uninfected subjects. After preparation of section and extraction of protein from antral biopsies, immunohistochemistry and western blot methods were used to evaluate the Th22 cells and IL-22 protein expression level, respectively. According to findings, the Th22 cells count and the IL-22 protein expression level in the infected subjects were siginficantly more than in the uninfected subjects. It should be noted that the Th22 cells count and the IL-22 protein expression level in the infected subjects with PUD were significantly greater than those in the infected subjects with gastritis. In addition, the Th22 cells count had positive correlation with the density of H. pylori, chronic inflammation score and acute inflammatory score in the infected subjects with PUD. The Th22 cells count had positive correlation with the Th17 cells count and inverse correlation with the Treg cells count in the infected subjects with PUD and gastritis. Our data demonstrated that abnormal hyper-activation of Th22 cells as well as its correlation with the Th17 cells during infection caused by H. pylori might damage tissues through immunopathological responses. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder mostly associated with IgE elevation and skin barrier dysfunction due to decreased filaggrin expression. The lesional skin of AD exhibits Th2- and Th22-deviated immune reactions that are progressive during disease chronicity. Th2 and Th22 cytokines further deteriorate the skin barrier by inhibiting filaggrin expression. Some IgEs are reactive to self-antigens. The IgE autoreactivity may precipitate the chronicity of AD. Upon activation of the ORAI1 calcium channel, atopic epidermis releases large amounts of thymic stromal lymphopoietin (TSLP), which initiates the Th2 and Th22 immune response. Th2-derived interleukin-31 and TSLP induce an itch sensation. Taken together, TSLP/Th2/Th22 pathway is a promising target for developing new therapeutics for AD. Enhancing filaggrin expression using ligands for the aryl hydrocarbon receptor may also be an adjunctive measure to restore the disrupted barrier function specifically for AD.

Background: CD4 + T cell responses in HCV infection have a crucial role in the immunopathology of hepatitis C virus (HCV) infection. Our aim was to investigate the frequency of Th1, Th17, and Th22 cells in HCV-infected patients and elucidate their role in the progression of the disease., Methods: Twenty-six HCV-infected patients and 26 healthy individuals were recruited. Peripheral blood mononuclear cells (PBMCs) were stained to separate CD4, IFN-γ, IL-17, and IL-22 producing cells using flow cytometry., Results: Results showed that the mean expression of IL-22 in CD4 + T cells was significantly lower in HCV-infected patients compared to healthy controls. About correlation with clinical factor and T subsets, a negative correlation between the frequency of CD4 + IFN-γ + cells and Thyroxine level (T4) was observed in the patients. The data showed a positive link between thyroid-stimulating hormone (TSH), cholesterol levels, and the frequency of Th17 cells. In addition, a positive correlation was seen between serum creatinine level with both Th1 and Th17. Ultimately, it was found that there was a positive link between viral burden and IL-17 + IL-22 + cells and a negative correlation between viral load and pure Th22., Conclusions: Our findings indicate that Th22 cells may play a part in the immunopathology of HCV and show the associations between Thelper subsets and the clinical signs of the disease., Competing Interests: None., (AJCEI Copyright © 2024.)

Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (T H 2/T H 22/T H 17/T H 1) and epidermal differentiation. We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including T H 2 (IL4 receptor [IL4R] , IL13 , CCL13 /monocyte chemoattractant protein 4, CCL17 /thymus and activation-regulated chemokine, CCL18 /pulmonary and activation-regulated chemokine, CCL22 /macrophage-derived chemokine, and CCL26 /eotaxin-3), T H 17/T H 22 (lipocalins, PI3 /elafin, CCL20 , S100A7 / S100A8 / S100A9 , and IL36G / IL36RN), and T H 1 (IFNG , CXCL9 / CXCL11 , and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. We sought to characterize age-related changes in the AD profile. We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P =.873), dendritic cell infiltrates (CD1b+ and FcεRI+, P <.05) decreased with age. T H 2 measures (IL5 , IL13 , CCL13 , CCL18 , and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with T H 2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = −0.24 and r = −0.23, respectively; P <.05). T H 22-secreted IL 22 expression levels also decreased with age uniquely in patients with AD (P <.05). Expression of T H 1-related (IFNG , IL12/23p40 , STAT1 , and CXCL9 ; P <.05 for CXCL9) and T H 17-related (IL 17A and IL 20 ; P <.05 for IL 20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG] , P <.05), whereas expression of S100As (S100A8 , P <.01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P <.05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with T H 2 downregulation (CCL26; r = −0.32, P <.1) and T H 1 upregulation (IFN-γ; r = 0.48, P <.01) with age. The adult AD profile varies with age. Although T H 1/T H 17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in T H 2/T H 22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD. [ABSTRACT FROM AUTHOR]

Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA)+ T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo. We sought to measure cytokine production by circulating skin-homing (CLA+) versus systemic (CLA−) "polar" CD4+/CD8+ ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects. Flow cytometry was used to measure levels of the cytokines IFN-γ, IL-13, IL-9, IL-17, and IL-22 in CD4+/CD8+ T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies. Patients with Vitiligo showed the highest CLA+/CLA− T H 1/type 1 cytotoxic T-cell polarization, with parallel T H 2/T H 9/T H 17/T H 22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P <.05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P <.001). Vitiligo severity correlated with levels of multiple cytokines (P <.1), whereas duration was linked with IFN-γ and IL-17 levels (P <.04). Patients and control subjects grouped into separate clusters based on blood biomarkers. Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

BACKGROUND: Th22 cells are a novel type of CD4+ helper T cells. Exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) have T cell immunomodulatory function. OBJECTIVE: To investigate the Th22 cell immunomodulatory ability of exosomes secreted from hUCMSCs． METHODS: hUCMSCs were isolated and cultured, and cell line was authenticated using short tandem repeat (STR) analysis. Exosomes were extracted from the supernatant of passage 4 hUCMSCs. Morphology and particle size of the exosomes were detected under transmission electron microscope. The expression of specific surface marker CD63 and CD81 were detected by western blot. The concentration of exosomes was evaluated by BCA assay. Cell activation cocktail stimulated peripheral blood mononuclear cells from healthy donors were co-cultured with exosomes for 6 hours. The percentage of Th22 cells and the proliferation of CD3++CD4+T cells and CD3++CD8+T cells were detected by flow cytometry. Flow cytometry was also used to test the level of interleukin 22 at 72 hours of co-culture. RESULTS AND CONCLUSION: Successfully established hUCMSCs primary cell line could stably passage. Exosomes secreted from hUCMSCs had typical exosomal morphology and marker proteins, and significantly inhibited the proliferation of CD3+CD4+T cells (P < 0.05) and CD3+CD8+T cells (P < 0.01). These exosomes also inhibited the proliferation of Th22 cells, and reduced the level of interleukin 22 in the cells (P < 0.01). These findings indicate that exosomes secreted from hUCMSCs inhibit Th22 cell expression and function, and have the immunomodulatory function of Th22 cells in vitro, which can be a new therapeutic agent for the treatment of immune disorders. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is a common form of non-scarring hair loss. The pathogenesis of AA is believed to involve multiple inflammatory cytokines, including possibly IL-17A. To assess the efficacy and safety of the IL-17A antagonist secukinumab in AA, we conducted a double-blinded, randomized prospective pilot study in which 11 subjects were treated with either secukinumab (n = 7) or placebo (n = 4) subcutaneously at weeks 0, 1, 2, 3, 4 and every 4 weeks thereafter until (inclusive of) week 20. The primary endpoint for the study was the percentage of patients achieving SALT50 at 24 weeks. A total of three subjects out of 11 completed the study through the primary endpoint, and therefore, we used the last observation carried forward method to analyze the missing data. At the primary endpoint or last completed observation, 0% (0/7) of the secukinumab-treated subjects achieved a 50% reduction in SALT score (SALT50), and likewise, 0% (0/4) of the placebo-treated subjects achieved SALT50. In the secukinumab group, one (14.3%) subject had some hair regrowth, one (14.3%) subject had worsening hair loss, and five (71.4%) subjects had no change in response to treatment. No adverse events attributable to the study drug were observed. The lack of a treatment response to most of our treated patients suggests that the TH17/IL-17 axis likely has no pathogenic role in AA and an alternative therapeutic approach should be considered for this disease. However, due to the low statistical power of this study, future studies may be required to corroborate these findings. [ABSTRACT FROM AUTHOR]

A new population of T cells known as Th22 was described for the first time in 2009. These cells are usually identified by the production of IL-22. However, this cytokine is also secreted by other cells such as Th1, Th2, Th17, natural killers, and innate lymphoid cells. Th22 is known as a pro-inflammatory agent in allergic skin diseases. Recently, more evidence has emerged showing associations between these cells and other diseases. The role of Th22 in asthma and allergic rhinitis is controversial: some authors suggest that Th22 has a pro-inflammatory effect, while others state that Th22 has anti-inflammatory properties. The aim of this article was to review the role of Th22 and IL-22 in allergic airway diseases based on the most recent literature. This review suggests that Th22 plays a significant role in the pathogenesis of allergic airway diseases and has predominantly anti-inflammatory properties. More studies are needed to clarify the role of Th22 in more detail. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a hematological malignancy in which the immune response serves a pivotal role in progression. Aryl hydrocarbon receptor (AHR) is involved in the modulation of the immune system, particularly in the differentiation of T‑helper cell (Th) subsets. Although the NLR family pyrin domain‑containing 3 (NLRP3) inflammasome has been implicated as essential in the pathogenesis of autoimmune and inflammatory diseases, the role it serves in the development of AML remains unknown. Therefore, in order to identify and describe the possible roles of AHR, as well as NLRP3 inflammasome, in the pathogenesis of AML and their relationship with Th subsets (Th1 Th22), the present study investigated the mRNA expression levels of AHR and NLRP3 inflammasome molecules in the peripheral blood and bone marrow. Concentrations of plasma IL‑18 were also investigated in peripheral blood by ELISA, as well as the proportions of Th22 and Th1. In the present study, there were three groups: Newly diagnosed (ND) patients; complete remission (CR); and normal controls. A markedly increased expression of NLRP3 inflammasome molecules in bone marrow mononuclear cells (BMMCs) from newly diagnosed (ND) patients compared with patients in complete remission (CR) was identified. NLRP3 inflammasome molecules were also observed to be aberrantly expressed in peripheral blood (PB) mononuclear cells (PBMCs), accompanied with aberrant interleukin (IL)‑18 levels in PB plasma. The relative level of IL‑18 mRNA became normal after the ND patients with AML achieved CR. In bone marrow, the expression of AHR was significantly higher in ND patients than in CR patients. Furthermore, the expression level of NLRP3 inflammasome molecules was significantly correlated with AHR expression in patients with AML. In the Th subsets, a significantly increased proportion of Th22 in PB from ND patients compared with CR patients or controls was identified, accompanied with decreased Th1. It was concluded that the NLRP3 inflammasome, associated with AHR, was involved in the development of AML and may have influenced the differentiation of Th subsets. [ABSTRACT FROM AUTHOR]

The involvement of T-helper (Th)1, Th17 and Th22 cell subsets, in immunity, as well as in pathological inflammatory reactions, makes it important to determine their relative proportion. A triple FluoroSpot detecting the hallmark cytokines of Th1 (IFN-γ), Th17 (IL-17A) and Th22 (IL-22) was developed and evaluated using human peripheral blood mononuclear cells from healthy donors incubated with tetanus toxoid, Candida albicans extract, mycobacterial purified protein derivative or medium only. Antigen stimulation yielded mainly cells secreting IFN-γ, IL-17A or IL-22 alone but lower proportions of double-secreting cells were also found; triple-secreting cells were rare. The response to C. albicans contrasted in that higher proportions of IL-17A single secreting as well as co-secreting cells, in particular IL-17A/IL-22, were found. The FluoroSpot analysis correlated well with single cytokine ELISpot assays ran in parallel and the methods displayed a comparable sensitivity. The results demonstrate the functionality of the FluoroSpot assay for simultaneous analysis of distinct Th1, Th17, Th22 as well as intermediate cell populations. The method provides a mean for a simple and rapid analysis of the involvement of these cells in immunity and disease.

Abstract. T cell populations, specifically, T helper (Th) cells, are among key players in the processes occurring in the body following exposure to a foreign antigen. Usage of new, highly sensitive instruments allowed of more detailed studies of their structural arrangement, as well as to detect a number of functionally significant minor subsets. These T cell subtypes were characterized both phenotypically and functionally. Present review article concerns Th thymic naїve subsets, Th central naїve subpoppulations, Th9, Th22, and CD4+CD8+ doublepositive T cells. Their role and functional significance is discussed in various pathological conditions. At present time, there are convincing data about specific arrays of membrane molecules, transcription factors, production of specific mediators typical to either of these subsets. Application of these markers in laboratory studies, will certainly improve diagnostic quality when evaluating functional alterations of immune system and adequacy of prescribed immunotherapy.