Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161+ T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161+ T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161+ T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161+ T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161+ T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161+CD103+ T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161+ T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161+CD8+ T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161+ T cells in the advancement and relapse of CRSwNPs.

OBJECTIVE: This study aimed to investigate the role of KLRB1 (CD161) in human CD4+ T cells and elucidate its significance in primary Sjögren\'s syndrome (pSS).
METHODS: Peripheral blood samples from 37 healthy controls and 44 pSS patients were collected. The publicly available single-cell RNA-Seq data from pSS patient PBMCs were utilized to analyse KLRB1 expression in T cells. KLRB1-expressing T lymphocyte subset proportions in pSS patients and healthy controls were determined by flow cytometry. CD25, Ki-67, cytokine secretion, and chemokine receptor expression in CD4+ KLRB1+ T cells were detected and compared with those in CD4+ KLRB1- T cells. Correlation analysis was conducted between KLRB1-related T-cell subsets and clinical indicators. ROC curves were generated to explore the diagnostic potential of KLRB1 for pSS.
RESULTS: KLRB1 was significantly upregulated following T-cell activation, and Ki-67 and CD25 expression was significantly greater in CD4+ KLRB1+ T cells than in CD4+ KLRB1- T cells. KLRB1+ CD4+ T cells exhibited greater IL-17A, IL-21, IL-22, and IFN-γ secretion upon stimulation, and there were significantly greater proportions of CCR5+, CCR2+, CX3CR1+, CCR6+, and CXCR3+ cells among CD4+ KLRB1+ T cells than among CD4+ KLRB1- T cells. Compared with that in HCs, KLRB1 expression in CD4+ T cells was markedly elevated in pSS patients and significantly correlated with clinical disease indicators.
CONCLUSIONS: KLRB1 is a characteristic molecule of the CD4+ T-cell activation phenotype. The increased expression of KLRB1 in the CD4+ T cells of pSS patients suggests its potential involvement in the pathogenesis of pSS and its utility as an auxiliary diagnostic marker for pSS.

OBJECTIVE: The purpose of this study was to examine the proportion of CD161 on CD56+ natural killer (NK) cells in peripheral blood of primary Sjögren\'s syndrome (pSS) and investigate its clinical relevance of pSS.
METHODS: The proportion of CD56+ NK cells and CD161 on CD56+ NK cells was detected by flow cytometry in 31 pSS patients and 29 healthy controls (HCs). The correlations between the proportion of CD161+CD56+ NK cells and clinical features and disease activity of pSS were further analyzed. Meanwhile, we drew the receiver operating characteristic curve to evaluate the diagnostic value of CD161+CD56+ NK cells in pSS. In addition, we evaluated the differences in the effects of CD161+ cells and CD161- cells in peripheral blood on the function of CD56+ NK cells in 5 pSS patients.
RESULTS: The proportion of CD56+ NK cells and CD161+CD56+ NK cells decreased markedly in pSS patients compared to HCs. The correlation analysis showed that the proportion of CD161+CD56+ NK cells negatively correlated with white blood cells, Immunoglobulin A (IgA), IgM, IgG, European League Against Rheumatism Sjogren\'s Syndrome Patient Reported Index and European League Against Rheumatism Sjogren\'s Syndrome Disease Activity Index, and positively correlated with complement C4. The proportion of CD161+CD56+ NK cells in pSS patients with decayed tooth, fatigue, arthralgia, skin involvement, primary biliary cirrhosis, interstitial lung disease, anti-SSA/Ro60 positive, anti-SSB positive and high IgG was lower than that in negative patients. Furthermore, compared with inactive patients, the proportion of CD161+CD56+ NK cells decreased obviously in active patients. The area under the curve was 0.7375 (p = .0016), the results indicated that CD161+CD56+ NK cells had certain diagnostic values for pSS. In addition, the proportion of CD86, HLA-DR, Ki67, FasL, TNF-α, and IFN-γ on CD161+CD56+ NK cells was lower than that on CD161-CD56+ NK cells in the peripheral blood of pSS patients.
CONCLUSIONS: This study suggested that the proportion of CD56+ NK cells and CD161+CD56+ NK cells decreased significantly in pSS patients, and the proportion of CD161+CD56+ NK cells negatively associated with the clinical features and disease activity of pSS patients. CD161 expression inhibited the function of CD56+ NK cells in peripheral blood of pSS patients. The CD161+CD56+ NK cells may present as a potential target for therapy and a biomarker of disease activity in pSS.

An active host adaptive response is characterized by the existence of programmed cell death protein 1 (PD-1)+ /IFN-γ+ cytotoxic T cells and IFN-γ-induced PD-L1+ tumor cells (TCs), which predicts high response rate to anti-PD-1/L1 therapy. Recently, CD161 and its ligand LLT1 (CLEC2D) have been identified as an emerging checkpoint for immunotherapy. Clarifying its heterogeneous clinical expression pattern and its immune landscape is a prerequisite for maximizing the response rate of CD161 blockade therapy in a specific population of oral squamous cell carcinoma (OSCC) patients. Here, we investigated the expression pattern of CD161/LLT1 and its association with major immunocytes (T cells, B cells, NK cells, and macrophages) by multiplex immunofluorescence, immunohistochemistry, and flow cytometry in 109 OSCC tissues and 102 peripheral blood samples. TCs showed higher LLT1 levels than tumor infiltrating lymphocytes (TILs), whereas CD161 was highly expressed in CD8+ T cells at the tumor front, which was decreased in paracancerous tissue. High expression of TC-derived LLT1 (LLT1TC ) conferred poor clinical outcomes, whereas higher CD161+ and LLT1+ TILs were associated with better prognosis. Meanwhile, patients with high LLT1TC showed a decreased ratio of CD8+ /Foxp3+ T cells in situ, but CD161+ TILs correlated with more peripheral CD3+ T cells. Interestingly, treatment of OSCC patients with nivolumab (anti-PD-1) could restore tumoral CD161/LLT1 signal. Furthermore, an OSCC subgroup characterized by high LLT1+ TCs and low CD161+ CD8+ T cells showed fewer peripheral T cells and a higher risk of lymph node metastasis, leading to a shorter 5-year survival time (29%). More LLT1TC at the invasive front was another risk characteristic of exhausted T cells. In conclusion, in view of this heterogeneity, the LLT1/CD161 distribution pattern should be determined before CD161-based immunotherapy.

CD161 has been linked to the appearance and development of various cancers.
The mutation map and the variation of CNVs and SNVs of CD161 were displayed according to cBioportal and GSCALite. We also evaluated the pathway enrichment and drug sensitivity of CD161 according to GSCALite. We performed a single-cell sequencing analysis of cancer cells and T cells in melanoma. The cell communication patterns related to CD161 were further explored. Multiplex immunofluorescence staining of tissue microarrays was used to detect the association between CD161 expression and macrophages and T cells.
A high CD161 level was related to neoantigens expression, pathway enrichment, and drug sensitivity. In addition, single-cell sequencing analysis showed that CD161 was mainly expressed in T cells, M1 and M2 Macrophages, neoplastic, microglial cells, neurons, and cancer cells in many tumor types. Further study on pseudotime trajectories and functional annotation of CD161 proved the critical role of CD161 in tumor progression and T cell immunity in melanoma. Multiplex immunofluorescence revealed that CD161 is closely correlated with the immune infiltration of T cells and macrophages in multiple cancers. In addition, high CD161 expression predicted a favorable immunotherapy response.
CD161 is involved in the immune infiltration of T cells and macrophages and might be a promising target for tumor immunotherapy.

Background: CD161 has been identified as a prognostic biomarker in many neoplasms, but its role in breast cancer (BC) has not been fully explained. We aimed to investigate the molecular mechanism and prognostic value of CD161 in BC. Methods: CD161 expression profile was extracted from TIMER, Oncomine, UALCAN databases, and verified by the Gene Expression Omnibus (GEO) database and quantitative real-time polymerase chain reaction (qRT-PCR). The prognostic value of CD161 was assessed via GEPIA, Kaplan-Meier plotter and PrognoScan databases. The Cox regression and nomogram analyses were conducted to further validate the association between CD161 expression and survival. Gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, and KEGG pathway enrichment analysis were performed to probe the tumor-associated annotations of CD161. CIBERSORT and ssGSEA were employed to investigate the correlation between CD161 expression and immune cell infiltration in BC, and the result was verified by TIMER and TISIDB. Results: Multiple BC cohorts showed that CD161 expression was decreased in BC, and a high CD161 expression was associated with a preferable prognosis. Therefore, we identified the combined model including CD161, age and PR status to predict the survival (C index = 0.78) of BC patients. Functional enrichment analysis indicated that CD161 and its co-expressed genes were closely related to several cancerous and immune signaling pathways, suggesting its involvement in immune response during cancer development. Moreover, immune infiltration analysis revealed that CD161 expression was correlated with immune infiltration. Conclusion: Collectively, our findings revealed that CD161 may serve as a potential biomarker for favorable prognosis and a promising immune therapeutic target in BC.

Proallergic type 2 helper T (Th2A) cells are a subset of memory Th2 cells confined to atopic individuals, and they include all the allergen-specific Th2 cells. Recently, many studies have shown that Th2A cells characterized by CD3+ CD4+ HPGDS+ CRTH2+ CD161high ST2high CD49dhigh CD27low play a crucial role in allergic diseases, such as atopic dermatitis (AD), food allergy (FA), allergic rhinitis (AR), asthma, and eosinophilic esophagitis (EoE). In this review, we summarize the discovery, biomarkers, and biological properties of Th2A cells to gain new insights into the pathogenesis of allergic diseases.

BACKGROUND: Glioblastoma is a paradigm of cancer-associated immunosuppression, limiting the effects of immune therapeutic strategies. Thus, identifying the molecular mechanisms underlying immune surveillance evasion is critical. Recently, the preferential expression of inhibitory NK-cell receptor CD161 on glioma-infiltrating cytotoxic T cells was identified. Focusing on the molecular annotated, large-scale clinical samples from different ethnic origins, the data presented here provide evidence of this immune modulator\'s essential roles in brain tumor biology.
METHODS: Retrospective RNA-seq data analysis was conducted in a cohort of 313 patients with glioma in the Chinese Glioma Genome Atlas database and 603 patients in the TCGA database. In addition, single-cell sequencing data from biosamples of functional studies, featuring seven surgical specimens of glioblastoma patients, thereof-derived glioma stem cells co-cultured with peripheral leukocytes were used to analyze gliomagenesis.
RESULTS: CD161 was enriched in high-grade gliomas and IDH wildtype glioma. CD161 acted as a potential biomarker for the mesenchymal subtype of glioma and an independent prognostic factor for the overall survival of patients with glioma. In addition, CD161 played an essential role in inhibiting the cytotoxicity of T cells in glioma patients. During the process of gliomagenesis, the expression of CD161 on different lymphocytes dynamically evolved.
CONCLUSIONS: The expression of CD161 was closely related to the pathology and molecular pathology of glioma. Meanwhile, CD161 promoted the progression and evolution of gliomas through its unique effect on T cell dysfunction. Thus, CD161 is a promising novel target for immunotherapeutic strategies of glioma.

Background: CD161 is a promising immune checkpoint mainly expressed on natural killer (NK) cells and is essential for immunoregulatory functions. However, it remains obscure how CD161 correlates with immune infiltration and patient prognosis in pan-cancer. Methods: We employed HPA, TCGA, GTEx, TIMER2.0, and GEPIA2 databases as well as R language to analyze and visualize CD161 in cancers. Our twenty-four glioma samples were sequenced for validation. Results: Overall, CD161 was differentially expressed between most paired cancer and normal controls. Higher CD161 expression was associated with poorer overall survival (OS) in the TCGA LGG (HR = 2.18, 95%CI = 1.79-2.66, P < 0.001) and UVM (HR = 1.32, 95%CI = 1.05-1.65, P = 0.016) cohorts. In these two cancer types, CD161 was significantly correlated with expression levels of recognized immune checkpoints and the abundance of markers of specific immune subsets, including CD8+ T cells, dendric cells (DCs), M2 macrophages, and exhausted T cells (Texs). In addition, CD161 was involved in several immune pathways in LGG and UVM, highlighting its role in regulating immune processes in the context of oncology. Conclusions: CD161 is a potential prognostic biomarker and immunotherapy target in human cancers, especially brain lower grade gliomas.

CD161, encoded by killer cell lectin-like receptor B1 gene, is a newly reported candidate inhibitor of tumour-infiltrating T cells. Antibody-mediated CD161 blockade enhances T cell-mediated killing of cancer cells in vitro and in vivo in several tumour types. We evaluated the role of CD161 using The Cancer Genome Atlas (TCGA) Pan-Cancer Data.
CD161 expression was analysed using RNAseq data from TCGA and the Genotype-Tissue Expression (GTEx) database. HPA, GeneCards, and String database were used to explore the protein information of CD161. The prognostic value of CD161 was analysed using clinical survival data from the TCGA. Enrichment analysis of CD161 was conducted using the R package \"clusterProfiler\". We downloaded the immune cell infiltration score of TCGA samples from published articles and online databases and performed a correlation analysis between immune cell infiltration levels and CD161 expression. We further assessed the association between CD161 and immune checkpoints, immune activating genes, immunosuppressive genes, chemokines, and chemokine receptors.
CD161 was differentially expressed and predicted better survival status in most tumour types in TCGA. In addition, CD161 expression was significantly associated with immunoregulatory interactions between lymphoid and non-lymphoid cells. CD161 expression was closely correlated with T cell infiltration, immune checkpoints, immune activating genes, immunosuppressive genes, chemokines, and chemokine receptors.
Our results suggest that CD161 is a potential cancer biomarker. CD161 might synergize with other immune checkpoints to regulate the immune microenvironment, which could be applied in the development of new-targeted drugs for immunotherapy.
This work was supported by the National Nature Science Foundation of China (grant numbers 81773008, 81672756, 81872399, 81972897), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2015), the Natural Science Foundation of Guangdong Province (grant number 2017A030311023), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program: 2017BT01S131 and the Guangzhou Technology Project (grant number 201804010044), National Key R&D Program of China (Grant Nos. 2020YFC2006400), Key-Area Research and Development Program of Guangdong Province (2019B020227004).