Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals.

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor ß chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1ß induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1ß to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1ßR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.

Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development.

Expression of tissue-restricted antigens (TRAs) in thymic epithelial cells (TECs) ensures negative selection of highly self-reactive T cells to establish central tolerance. Whether some of these TRAs could exert their canonical biological functions to shape thymic environment to regulate T cell development is unclear. Analyses of publicly available databases have revealed expression of transcripts at various levels of many cytokines and cytokine receptors such as IL-15, IL-15Rα, IL-13, and IL-23a in both human and mouse TECs. Ablation of either IL-15 or IL-15Rα in TECs selectively impairs type 1 innate like T cell, such as iNKT1 and γδT1 cell, development in the thymus, indicating that TECs not only serve as an important source of IL-15 but also trans-present IL-15 to ensure type 1 innate like T cell development. Because type 1 innate like T cells are proinflammatory, our data suggest the possibility that TEC may intrinsically control thymic inflammatory innate like T cells to influence thymic environment.

Identification of an Immune-Related Gene Signature Based on Immunogenomic Landscape Analysis to Predict the Prognosis of Adult Acute Myeloid Leukemia Patients.

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by highly heterogeneous molecular lesions and cytogenetic abnormalities. Immune disorders in AML and impaired immune cell function have been found to be associated with abnormal karyotypes in AML patients. Immunotherapy has become an alternative therapeutic method that can improve the outcomes of AML patients. For solid tumors, the expression patterns of genes associated with the immune microenvironment provide valuable prognostic information. However, the prognostic roles of immune genes in AML have not been studied as yet. In this study, we identified 136 immune-related genes associated with overall survival in AML patients through a univariate Cox regression analysis using data from TCGA-AML and GTEx datasets. Next, we selected 24 hub genes from among the 136 genes based on the PPI network analysis. The 24 immune-related hub genes further underwent multivariate Cox regression analysis and LASSO regression analysis. Finally, a 6 immune-related gene signature was constructed to predict the prognosis of AML patients. The function of the hub IRGs and the relationships between hub IRGs and transcriptional factors were investigated. We found that higher levels of expression of CSK, MMP7, PSMA7, PDCD1, IKBKG, and ISG15 were associated with an unfavorable prognosis of AML patients. Meanwhile, patients in the TCGA-AML datasets were divided into a high risk score group and a low risk score group, based on the median risk score value. Patients in the high risk group tended to show poorer prognosis [P = 0.00019, HR = 1.89 (1.26-2.83)]. The area under the curve (AUC) was 0.6643. Multivariate Cox Regression assay confirmed that the 6 IRG signature was an independent prognostic factor for AML. The prognostic role of the immune related-gene signature was further validated using an independent AML dataset, GSE37642. In addition, patients in the high risk score group in the TCGA dataset were found to be of an advanced age, IDH mutation, and M5 FAB category. These results suggested that the proposed immune related-gene signature may serve as a potential prognostic tool for AML patients.

Identification of an autophagy-related gene signature for survival prediction in patients with cervical cancer.

Cervical cancer is one of the most common female malignancy that occurs worldwide and is reported to cause over 300,000 deaths in 2018. Autophagy controls the survival and death of cancerous cells by regulating the degradation process of cytoplasm and cellular organelle. In the present study, the differentially expressed autophagy-related genes (ARGs) between healthy and cancerous cervical tissues (squamous cell neoplasms) were obtained using data from GTEx and The Cancer Genome Atlas (TCGA) database. The functionalities of the differentially expressed ARGs were analyzed using Gene Ontology (GO) as well as the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Next, we conducted univariate Cox regression assay and obtained 12 ARGs that were associated with the prognosis of cervical cancer patients. We carried out a multivariate Cox regression analysis and developed six ARG-related prognostic signature for the survival prediction of patients with squamous cell cervical cancer (Risk score = - 0.63*ATG3-0.42*BCL2 + 0.85*CD46-0.38*IFNG+ 0.23*NAMPT+ 0.82*TM9SF1). Following the calculation of risk score using the signature, the patients were divided into high and low-risk groups according to the median value. Kaplan-Meier curve demonstrated that patients with a high-risk score tend to have a poor prognosis (P < 0.001). The value for area under the curves corresponding to the receiver operating characteristic (ROC) was 0.740. As observed, the expression of IFNG was negatively associated with lymph node metastasis (P = 0.026), while a high-risk score was significantly associated with increased age (P = 0.008). To further validate the prognostic signature, we carried out a permutation test and confirmed the performance of the risk score. In conclusion, our study developed six ARG-related prognostic signature for patients with squamous cell cervical cancer, which might help in improving the prognostic predictions of such patients.

Graded diacylglycerol kinases α and ζ activities ensure mucosal-associated invariant T-cell development in mice.

Mucosal-associated invariant T (MAIT) cells participate in both protective immunity and pathogenesis of diseases. Most murine MAIT cells express an invariant TCRVα19-Jα33 (iVα19) TCR, which triggers signals crucial for their development. However, signal pathways downstream of the iVα19TCR and their regulation in MAIT cells are unknown. Diacylglycerol (DAG) is a critical second messenger that relays the TCR signal to multiple downstream signaling cascades. DAG is terminated by DAG kinase (DGK)-mediated phosphorylation and conversion to phosphatidic acid. We have demonstrated here that downregulation of DAG caused by enhanced DGK activity impairs late-stage MAIT cell maturation in both thymus and spleen. Moreover, deficiency of DGKζ but not DGKα by itself causes modest decreases in MAIT cells, and deficiency of both DGKα and ζ results in severe reductions of MAIT cells in an autonomous manner. Our studies have revealed that DAG signaling is not only critical but also must be tightly regulated by DGKs for MAIT cell development and that both DGKα and, more prominently, DGKζ contribute to the overall DGK activity for MAIT cell development.

Differential Control of iNKT Cell Effector Lineage Differentiation by the Forkhead Box Protein O1 (Foxo1) Transcription Factor.

The invariant NKT (iNKT) cells recognize glycolipid antigens presented by the non-classical MHC like molecule CD1d. They represent an innate T-cell lineage with the ability to rapidly produce a variety of cytokines in response to agonist stimulation to bridge innate and adaptive immunity. In thymus, most iNKT cells complete their maturation and differentiate to multiple effector lineages such as iNKT-1, iNKT-2, and iNKT-17 cells that possess the capability to produce IFNγ, IL-4, and IL-17A, respectively, and play distinct roles in immune responses and diseases. Mechanisms that control iNKT lineage fate decisions are still not well understood. Evidence has revealed critical roles of Foxo1 of the forkhead box O1 subfamily of transcription factors in the immune system. However, its role in iNKT cells has been unknown. In this report, we demonstrate that deletion of Foxo1 causes severe decreases of iNKT cell total numbers due to impairment of late but not early iNKT cell development. Deficiency of Foxo1 results in decreases of iNKT-1 but increases of iNKT-17 cells. Our data reveal that Foxo1 controls iNKT effector lineage fate decision by promoting iNKT-1 but suppressing iNKT-17 lineages.

Deficiency of Mucosal-Associated Invariant T Cells in TCRJα18 Germline Knockout Mice.

Mucosal-associated invariant T (MAIT) cells and invariant NK T (iNKT) cells account for the major lymphocyte populations that express invariant TCRα-chains. MAIT cells mostly express the TCRVα19-Jα33 TCR in mice and the TCRVα7.2-Jα33 TCR in humans, whereas iNKT cells express the TCRVα14-Jα18 TCR in mice and the TCRVα24-Jα18 TCR in humans. Both MAIT and iNKT cells have the capacity to quickly produce a variety of cytokines in response to agonist stimuli and to regulate both innate and adaptive immunity. The germline TCRJα18 knockout (Traj18-/- ) mice have been used extensively for studying iNKT cells. Although it has been reported that the TCRα repertoire was narrowed and the level of Trav19-ja33 transcript was decreased in this strain of mice, direct assessment of MAIT cells in these mice has not been reported. We demonstrate in this study that this strain of mice is also defective of MAIT T cells, cautioning data interpretation when using this strain of mice.

Efficacy and safety of negative pressure versus natural drainage after thyroid surgery: A systematic review and meta-analysis.

BACKGROUND: To evaluate whether negative pressure drainage has advantage over natural drainage in effectiveness and safety for patients with thyroid disease after thyroid surgery. METHOD: We performed intensive literature search and followed the standards described in preferred reporting items for systematic review and meta-analysis (PRISMA) statement to conduct this systematic review. Risk of bias was assessed using the Cochrane Risk of bias tool. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to evaluate the quality of evidence body. RESULTS: Total 1195 participants with thyroid disease from 13 studies were included. For patients underwent thyroidectomy without neck dissection, negative pressure drainage group has a lower risk of seroma and wound infection. The duration of tube placement was shorter in negative pressure drainage group, which produced more fluid than natural drainage in the first 24-hour period. The effect of negative pressure drainage on reoperative rates, mortality, and length of hospitalization remains unclear. CONCLUSIONS: For patients underwent thyroidectomy with neck dissection, the difference between negative and natural pressure drainage groups remains uncertain due to sparse data. The quality of evidence for the above findings is low. The risk of bias for the studies is also serious. Therefore, more randomized or non-randomized controlled trials with larger sample sizes are required.

The effect of no drainage in patients who underwent thyroidectomy with neck dissection: A systematic review and meta-analysis.

BACKGROUND: To evaluate the effect of no drainage in patients who underwent thyroidectomy and neck lymph node dissection. METHODS: We followed the methodological standard expected by Cochrane. We searched the following databases by March 23, 2017: PubMed, The Cochrane Library, EMBASE via Ovid SP, and Medline via Ovid SP. Two reviewers screened the studies and extracted the data. Randomized controlled trials (RCTs) or nonrandomized interventional studies assessing the effect of no drainage following thyroidectomy with lymph node dissection were included. RESULTS: Three studies with 387 participants were included. There was no statistical difference between groups for the overall perioperative complications (2 RCTs, n = 234, RR 1.56, 95% CI 0.53-4.64), or specific complications such as seroma (2 RCTs, n = 234, RR 1.81, 95% CI 0.46-7.07), hematoma (2 RCTs, n = 234, RR 0.72, 95% CI 0.11-4.83) or hemorrhage (1 RCT, n = 69, RR 0.29, 95% CI 0.01-6.87). One case required reoperation due to hemorrhage in the drainage group was reported in 1 study (n = 32). No mortality was reported. Two studies (n = 234) stated a longer hospital stay in the drainage group than that in the group without drainage. There was moderate or serious bias for the risk of bias of included studies. CONCLUSION: The effect of no-drainage in patients with thyroid cancer who received thyroidectomy with neck dissections remains uncertain, since there are very few studies that addressed the question. Drainage may lead to longer hospital stay than nondrainage. More randomized or nonrandmized studies are required to address this issue.