Alignment of single-cell RNA-seq samples without overcorrection using kernel density matching.

Single-cell RNA sequencing (scRNA-seq) technology is poised to replace bulk cell RNA sequencing for many biological and medical applications as it allows users to measure gene expression levels in a cell type-specific manner. However, data produced by scRNA-seq often exhibit batch effects that can be specific to a cell type, to a sample, or to an experiment, which prevent integration or comparisons across multiple experiments. Here, we present Dmatch, a method that leverages an external expression atlas of human primary cells and kernel density matching to align multiple scRNA-seq experiments for downstream biological analysis. Dmatch facilitates alignment of scRNA-seq data sets with cell types that may overlap only partially and thus allows integration of multiple distinct scRNA-seq experiments to extract biological insights. In simulation, Dmatch compares favorably to other alignment methods, both in terms of reducing sample-specific clustering and in terms of avoiding overcorrection. When applied to scRNA-seq data collected from clinical samples in a healthy individual and five autoimmune disease patients, Dmatch enabled cell type-specific differential gene expression comparisons across biopsy sites and disease conditions and uncovered a shared population of pro-inflammatory monocytes across biopsy sites in RA patients. We further show that Dmatch increases the number of eQTLs mapped from population scRNA-seq data. Dmatch is fast, scalable, and improves the utility of scRNA-seq for several important applications. Dmatch is freely available online.

CD147 regulates the formation and function of immune synapses.

CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell activation and IS formation remains unclear. In the present study, we demonstrated that CD147 translocated to the IS upon T cell activation and was primarily distributed in the peripheral super molecular cluster (p-SMAC). The knock down of CD147 expression in T cells, but not in B cells, impaired IS formation. CD147 participated in IS formation between T cells and different types of antigen-presenting cells (APCs), including macrophages and dendritic cells. Ligation of CD147 with its monoclonal antibody (mAb) HAb18 effectively inhibited T cell activation and IL-2 secretion. CD98, a critical molecule interacting with CD147, was distributed in IS in a CD147-dependent way. Phosphorylation levels of T cell receptor (TCR) related molecules, like ZAP-70, ERK, and cJun, were down-regulated by CD147 ligation, which is crucial for the interaction of CD147 and TCR signaling transduction. CD147 is indispensable for the formation of immune synapses and plays an important role in the regulation of its function.

Functional Defects of Treg Cells: New Targets in Rheumatic Diseases, Including Ankylosing Spondylitis.

PURPOSE OF REVIEW: This study aims to review the advances of Treg cell biology, the functional defects of Treg cells, and the potential strategies for the experimental, preclinical or clinical application of Treg cell therapy in the context of autoimmune/immune-mediated rheumatic diseases. RECENT FINDINGS: CD4+CD25+ regulatory T (Treg) cells are a phenotypically and functionally heterogeneous subset of lymphocytes that prevent a variety of autoimmune diseases. As in many autoimmune diseases, the functional defects of Treg cells are supposed to play relevant roles in the pathogenesis and development of systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, and other autoimmune/immune-mediated rheumatic diseases. Consequently, manipulation and modulation of Treg cells represent a potent strategy for therapeutic benefit in many such diseases. A further understanding of the functional defects of Treg cells in rheumatic diseases will contribute to find new targets and therapies in rheumatic diseases, including ankylosing spondylitis.

Factors Associated with Caregiver Burden in Primary Caregivers of Patients with Adolescent Scoliosis: A Descriptive Cross-Sectional Study.

BACKGROUND Primary caregivers for patients with scoliosis suffer from considerable distress and burden. However, a few studies have examined the factors related to burden of caregivers of patients with adolescent scoliosis, particularly in China. Therefore, the present study aimed to identify patient and caregiver characteristics associated with caregiver burden. MATERIAL AND METHODS A cross-sectional study was conducted in a sample comprising 87 pairs of patients with adolescent scoliosis and their primary caregivers from July 2014 to October 2016 in Xi'an, China. Patients and their primary caregivers were administered a sociodemographic questionnaire. The caregiver burden, social support, and self-efficacy were assessed using the Chinese version of the Zarit Burden Interview (ZBI), Social Support Rating Scale (SSRS), and General Self-Efficacy Scale (GSE). A multivariate analysis was used to evaluate the factors associated with caregiver burden. RESULTS Most primary caregivers observed in this study were female (65.5%), with mothers of the patients accounting for 58.6% of all the caregivers. The ZBI score of primary caregivers was 36.83±13.30, and most caregivers (88.5%) had moderate or severe burden. The factors associated with caregiver burden were Cobb angle of patients, SSRS scores, GSE scores, and monthly household income per capita of the caregiver (R²=0.556; P<0.001). The identified significant factors explained nearly 56% of the variance in the caregiver burden. CONCLUSIONS The data indicated that most primary caregivers for patients with scoliosis had a considerable caregiver burden, and intervention of social support and self-efficacy might be helpful in reducing caregiver burden.

Circulating Angiogenic T Cells Are Increased in Lupus Nephritis Patients.

BACKGROUND Patients with systemic lupus erythematosus (SLE), especially with lupus nephritis (LN), undergo vascular damage and repair during the course of the disease. Since the recently identified angiogenic T cells (Tang) are involved in endothelial repair coupled with endothelial progenitor cells (EPCs), this study investigated the circulating Tang cells in LN patients and their potential correlations with disease features. MATERIAL AND METHODS Circulating Tang cells and EPCs were assessed by flow cytometry in peripheral blood samples from 67 SLE patients; of these, 32 had LN and 30 were matched healthy controls (HCs). The plasma levels of interleukin IL-17, IL-8, and vascular endothelial growth factor (VEGF) were quantified by immunoassays. RESULTS The percentage of circulating Tang cells in LN patients was significantly increased as compared to the non-LN patients and HCs, and they were positively correlated with the level of EPC and VEGF. Additionally, circulating Tang cell percentages were positively correlated with the extent of proteinuria in LN patients. CONCLUSIONS The increased levels of circulating Tang cells in LN patients might play a role in the balance of endothelium dysfunction in these patients.

Circulating Angiogenic T Cells and Their Subpopulations in Patients with Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with accelerated atherosclerosis and increased cardiovascular risk. Angiogenic T cells (Tang), a specific T cell subset, have been identified and involved in the repair of damaged endothelium. This study aimed to analyze the Tang cell subsets in relation to disease specific features from SLE patients. METHODS: Tang cell subsets were assessed in peripheral blood samples from 41 SLE patients and 22 healthy controls (HC) by flow cytometry on the basis of CD31 and CXCR4 expression on CD3+, CD4+, and CD8+ T cells. RESULTS: The percentage of circulating CD8+CD31+CXCR4+ T cells (CD8+ Tang), but not CD3+CD31+CXCR4+ T cells (Tang) and CD4+CD31+CXCR4+ T cells (CD4+ Tang), in SLE was higher than HC. The percentages of Tang cell subsets in anti-dsDNA-positive SLE patients were significantly increased as compared to their negative counterparts and HC. Additionally, the levels of circulating Tang cell subsets were negatively correlated with age at sampling and at diagnosis, but not disease duration or disease activity. CONCLUSION: Anti-dsDNA-positivity may identify a group of SLE patients with increased Tang cell subsets and circulating CD8+ Tang cells may be viewed as a potentially useful biomarker of endothelial damage and cardiovascular risk in SLE.

Enhancement of CD147 on M1 macrophages induces differentiation of Th17 cells in the lung interstitial fibrosis.

Lung interstitial fibrosis is a chronic lung disease, and few effective therapies are available to halt or reverse the progression of the disease. In murine and human lung fibrosis, the expression of CD147 is increased. However, the role of CD147 in lung fibrosis has not been identified, and it remains to be determined whether lung fibrosis would be improved by decreasing the expression of CD147. A murine bleomycin-induced lung interstitial fibrosis model was used in the experiments, and HAb18 mAbs and CsA were administered during the induction of lung fibrosis. In our study, we found that the HAb18 mAbs markedly reduced the collagen score and down-regulated M1 macrophages and Th17 cells. In vitro, flow cytometry analysis showed that M1 macrophages induced higher Th17 differentiation than M2 macrophages. After treatment with HAb18 mAbs or after reducing the expression of CD147 by lentivirus interference in M1 macrophages, the level of Th17 cells were significantly inhibited. In conclusion, HAb18 mAbs or CsA treatment ameliorates lung interstitial fibrosis. CD147 promoted M1 macrophage and induced the differentiation of Th17 cells in lung interstitial fibrosis, perhaps by regulating some cytokines such as IL-6, IL-1ß, IL-12 and IL-23. These results indicated that CD147 may play an important role in the development of lung interstitial fibrosis.

Kinetic changes of regulatory B10 cells in collagen-induced arthritis could be regulated by cytokines IFN-γ and TGF-ß1.

OBJECTIVE: The status of B10 cells in patients with rheumatoid arthritis (RA) has not been consistently reported. In this study, we observed the kinetic changes of the B10 cells in collagen-induced arthritis (CIA) mice and the influence of multiple cytokines on the B10 cells to investigate the potential mechanism underlying the changes of B10 cells. METHODS: The kinetic changes of frequency and function of the CD19(+)CD1d(hi)CD5(+) cells in splenic cells were observed during the complete progress of CIA mice. The kinetic changes of cytokines IL-4, IL-6, IL-17A, IL-18, TNF-α, IFN-γ and TGF-ß1 were also detected. Then influence of these cytokines on the status of B10 cells was investigated both in vitro and in vivo. RESULTS: The frequency and suppressive ability of the CD19(+)CD1d(hi)CD5(+) cells increased to its peak on the 14th day while gradually decreased subsequently. IFN-γ showed a similar tendency with the CD19(+)CD1d(hi)CD5(+) cells, whereas IL-6, IL-17A, IL-18, TNF-α, and TGF-ß1 reached its peak on the 28-35th day. In addition, IFN-γ up-regulated while TGF-ß1 down-regulated the frequency and function of the CD19(+)CD1d(hi)CD5(+) cells both in vitro and in vivo. CONCLUSION: The B10 cells in CIA mice could be regulated by IFN-γ and TGF-ß1, suggesting that the status of B10 cells in RA may be influenced by the balance of pro-inflammatory and anti-inflammatory factors, and the impaired B10 cells could be recovered in vitro by adequate treatment before being used for a therapeutic method in clinical practice.

Percentages of CD4+CD161+ and CD4-CD8-CD161+ T cells in the synovial fluid are correlated with disease activity in rheumatoid arthritis.

OBJECTIVE: CD161 has been identified as a marker of human IL-17-producing T cells that are implicated in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the potential link between the percentage of CD161+ T cells and disease activity in RA patients. METHODS: Peripheral blood (PB) from 54 RA patients and 21 healthy controls was evaluated. Paired synovial fluid (SF) (n = 17) was analyzed. CD161 expression levels on CD4+, CD8+, and CD4-CD8- T cells were assessed by flow cytometry. RESULTS: The percentage of CD4+CD161+ T cells in RA SF was higher than RA PB, and it was positively correlated with DAS28, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). CD4-CD8-CD161+ T cell percentage was decreased in RA PB and was further reduced in RA SF, and its level in SF was inversely correlated with DAS28, ESR, and CRP. However, CD8+CD161+ T cell percentage was neither changed in RA PB and SF nor correlated with disease activity indices. CONCLUSION: An increased CD4+CD161+ T cell percentage and a decreased CD4-CD8-CD161+ T cell percentage are present in RA SF and are associated with disease activity, and the accumulation of CD4+CD161+ T cells in SF may contribute to the local inflammation of RA.

Expression and prognostic significance of p21-activated kinase 6 in hepatocellular carcinoma.

BACKGROUND: p21-activated protein kinase (PAK) 6 is a serine-threonine kinase belonging to the PAK family. Previous studies have indicated that abnormal expressions of PAK1, PAK2, and PAK5 played critical roles in hepatocellular carcinoma (HCC). Recent studies suggested that deregulation of PAK6 expression played an important role in oncogenesis. To explore the potential roles of PAK6 in HCC, expression of PAK6 was detected in human HCC specimens. METHODS: Immunohistochemistry and Western blot analysis were performed for PAK6 in 121 HCC samples. The data were correlated with clinicopathologic features. The univariate and multivariate survival analyses were also performed to determine their clinical prognostic significance. RESULTS: PAK6 was overexpressed in HCC as compared with the adjacent noncancerous liver tissues. High expression of PAK6 was associated with Edmondson-Steiner grade (P = 0.006) and number of tumor nodules (P < 0.001), and PAK6 was positively correlated with proliferation marker Ki-67 (P < 0.01). Univariate analysis suggested that PAK6 expression was associated with poor prognosis (P < 0.001). Multivariate analysis indicated that PAK6 and Ki-67 protein expressions were independent prognostic markers for HCC (P = 0.0245 and 0.0331, respectively). CONCLUSIONS: Our results suggest that PAK6 overexpression is involved in the pathogenesis of HCC; it may be an independent poor prognostic factor for HCC.

Frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells correlate with disease activity in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a common autoimmune disease that is primarily driven by effector T cells, particularly Th17 cells, which are mainly contained within CD4+CD161+ T cells. Thus, we aimed to explore whether the frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells were correlated with RA disease activity. METHODS: The surface phenotype and cytokine production of blood were analyzed by flow cytometry in 52 RA patients and 17 healthy controls. The disease activity was evaluated by the 28-joint disease activity score. RESULTS: The frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells were increased in RA patients, and they were elevated in patients with active disease status compared to patients with low disease status. Furthermore, their frequencies were positively correlated with disease activity parameters. Receiver operating characteristic curve analysis revealed that IL-17-producing CD4+CD161+ T cell levels were able to distinguish disease activity with 60.7 % sensitivity and 87.5 % specificity, while CD4+CD161+ T cell levels showed 92.9 % sensitivity and 66.7 % specificity. CONCLUSION: These results support the hypothesis that Th17 cells are involved in the pathogenesis of RA and suggest that circulating CD4+CD161+ T cells are a potential biomarker of RA disease activity.

Frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells correlate with disease activity in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a common autoimmune disease that is primarily driven by effector T cells, particularly Th17 cells, which are mainly contained within CD4+CD161+ T cells. Thus, we aimed to explore whether the frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells were correlated with RA disease activity. METHODS: The surface phenotype and cytokine production of blood were analyzed by flow cytometry in 52 RA patients and 17 healthy controls. The disease activity was evaluated by the 28-joint disease activity score. RESULTS: The frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells were increased in RA patients, and they were elevated in patients with active disease status compared to patients with low disease status. Furthermore, their frequencies were positively correlated with disease activity parameters. Receiver operating characteristic curve analysis revealed that IL-17-producing CD4+CD161+ T cell levels were able to distinguish disease activity with 60.7 % sensitivity and 87.5 % specificity, while CD4+CD161+ T cell levels showed 92.9 % sensitivity and 66.7 % specificity. CONCLUSION: These results support the hypothesis that Th17 cells are involved in the pathogenesis of RA and suggest that circulating CD4+CD161+ T cells are a potential biomarker of RA disease activity.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Meplazumab in hospitalized adults with severe COVID-19 (DEFLECT): a multicenter, seamless phase 2/3, randomized, third-party double-blind clinical trial.

Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.

[Increased expression of inhibitor of differentiation 2 (Id2) in CD4+T cells in joint synovial fluid of patients with rheumatoid arthritis].

Objective To investigate the effect of inhibitor of differentiation 2 (Id2) on the proportion of CD4+T cells by detecting the proportion of CD4+T cell subsets and Id2 expression in peripheral blood and joint synovial fluid of patients with rheumatoid arthritis (RA). Methods A total of 51 RA patients (including 18 patients providing synovial fluid) and 31 healthy controls (HCs) were enrolled. The proportions of CD4+T cells, Th1 cells, and Th17 cells, and their expression of Id2 in peripheral blood and synovial fluid of RA patients and HCs were detected by flow cytometry. Results Compared with HCs group, the proportions of circulating CD4+T cells, Th1 cells, and Th17 cells and their expression of Id2 in RA patients did not change significantly. The proportions of CD4+T cells and Th1 cells, and Id2 expression in CD4+T cells in synovial fluid of RA patients were significantly higher than those in peripheral blood of RA patients and HCs. The expression rate of Id2 in CD4+T cells was positively correlated with the expression of IFN-γ, but not with erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and Disease Activity Score 28 (DAS28). Conclusion CD4+T cells are enriched in RA synovial fluid, and their Id2 expression may promote Th1 cell differentiation.

Th1-Like Treg Cells Are Increased But Deficient in Function in Rheumatoid Arthritis.

Objectives: This study aimed to investigate the changes in quantity and function of T helper (Th)-like T regulatory (Treg) cell subsets in peripheral blood (PB) and synovial fluid (SF) of rheumatoid arthritis (RA) patients and to understand their relationship with disease activity. Methods: A total of 86 RA patients and 76 gender and age-matched healthy controls (HC) were enrolled in this study. Th-like Treg frequency and function were determined using flow cytometry. The inhibitory function of Th-like Treg cells was detected using an in vitro co-culture suppression assay. Results: The proportion and absolute number of Th1-like Treg cells from RA PB and RA SF were significantly higher than those of HC PB. In RA SF, the proportions of Treg cells and Th1-like Treg cells were significantly lower in the elevated erythrocyte sedimentation rate or the C-Reactive Protein group, and in the positive groups of anti-CCP antibody and anti-MCV antibody. Additionally, the proportions of Treg cells and Th1-like Treg cells from RA SF were negatively correlated with disease activity. However, the expression levels of CD73 and TGF-ß1 in Th1-like Treg cells were decreased, and these Treg cells could not effectively inhibit the proliferation of effector T (Teff) cells. Conclusion: Our data indicate that Th1-like Treg cells are the predominant Treg cell subset in RA SF, but their suppressive function is defective. Improving the function of Th1-like Treg cells may control inflammation in joints and provide new strategies for Treg-targeted therapies in RA.

TNF-α inhibitor ameliorates immune-related arthritis and pneumonitis in humanized mice.

Objectives: This study aimed at establishing a mouse model of immune-related adverse in humanized BALB/c-hPD1/hCTLA4 mice to investigate their potential pathogenesis and explore therapeutic targets for immune-related arthritis and pneumonitis. Methods: Humanized BALB/c-hPD1/hCTLA4 mice were injected with vehicle or collagen-specific antibodies (CA) and immune checkpoint inhibitors (ICI, ipilimumab, anti-human CTLA-4; and nivolumab, anti-human PD-1), and some mice were treated with anti-TNF-α antibody, leading to the control, collagen antibody-induced arthritis (CAIA), CAIA+ICI and treatment groups. The severity of clinical arthritis and pneumonitis in mice was monitored longitudinally and the pathological changes in the joints and lungs were histologically analyzed and the contents of lung hydroxyproline were measured. The frequency of different subsets of T cells was analyzed by flow cytometry and multiplex immunofluorescency. Results: Compared with the control, the ICI group of mice developed the delayed onset of moderate degrees of arthritis while the CAIA+ICI group of mice exhibited the early onset of severe arthritis. Treatment with ICI caused severe pneumonitis, especially in the mice with CA. Flow cytometry analysis indicated a significantly higher frequency of splenic TNF-α+CD4+ and TNF-α+CD8+ T cells, but not other subsets of T cells tested, in the CAIA+ICI group of mice, relative to that in other groups of mice. Treatment with anti-TNF-α significantly mitigated the severity of arthritis and pneumonitis as well as deposition of collagen in lung of mice. The treatment also decreased the frequency of TNF-α+CD4+ and TNF-α+CD8+ T cells as well as effector memory T cells in the periphery lymph orangs and lungs of mice. Conclusions: We successfully established a humanized mouse model of ICI-related severe arthritis and pneumonitis with a higher frequency of TNF-α+ T cells, which were significantly mitigated by anti-TNF-α treatment. Conceptually, ICI treatment can induce multiple autoimmune-like diseases in autoimmune-prone individuals and TNF-α+ T cells may be therapeutic targets for intervention of immune-related arthritis and pneumonitis.

CD147-specific chimeric antigen receptor T cells effectively inhibit T cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is invasive and heterogeneous, and existing therapies are sometimes unsuccessful. Chimeric antigen receptor (CAR) T cell therapy is a breakthrough tumor treatment method, particularly for B cell acute lymphoblastic leukemia. We found that CD147 was highly expressed in tumor T cells of T-ALL patients and T cell lymphoma. Therefore, CD147-CAR T cells that contain a humanized single-chain variable fragment targeting human CD147 and a second-generation CAR frame were constructed for treating T-ALL. CD147-CAR T cells were able to maintain a healthy proliferation rate, preserving a subset of CD62L+/CCR7+ memory T cells. CD147-CAR T cells showed a potent anti-tumor activity against human T-ALL cell line and T-ALL blasts, releasing high level of cytokines in the process. However, CD147-CAR T cells exhibited potential safety toward human normal cells and CD147-deficent cells. NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt mice were used to establish a T-ALL xenograft model and CD147-CAR T cells conferred robust protection against T-ALL progression and significantly improved survival in mice. Overall, we found that CD147 is a potential antigen target of CAR T cell therapy for T-ALL.

[Research progresses on the function of tissue-resident regulatory T cells (trTregs)].

Regulatory T cells (Tregs) specifically express forkhead box P3 (FOXP3) and CD25, which are indispensable components in the immune system to maintain immune self-tolerance and homeostasis. In recent years, Tregs that exist in non-lymphatic tissues have gradually obtained people's attention. Through genomics, proteomics, metabolic regulation and other in vivo and in vitro functional studies, it has been found that tissue-resident Tregs have unique phenotype that are different from circulating Tregs, and can perform some non-immune functions in addition to its immunosuppressive function in the tissues. By summarizing various functions of non-lymphoid tissue Tregs, we aimed to provide reference for studies on the functional mechanism of tissue-resident Tregs and treatment targeting tissue-resident Tregs.

Regulatory T cell heterogeneity and therapy in autoimmune diseases.

Regulatory T (Treg) cells are a group of CD4+ T cell with high expression of CD25 and cell linage specific transcription factor forkhead box P3 (Foxp3) and play a vital role in maintaining immune homeostasis. In the last two decades, researchers have shown that Treg cells involved in the occurrence, development and prognosis of many diseases, especially in autoimmune diseases. Treg targeted therapies, such as low-dose interleukin-2 (IL-2) treatment and Treg infusion therapy, which are aimed at restoring the number or function of Treg cells, have become a hot topic in clinical trials of these diseases. It is believed that Treg cells are heterogeneous. Different subsets of Treg cells have various functions and play different parts in immunomodulatory. Gaining insights into Treg heterogeneity will help us further understand the function of Treg cells and provide news ideas for the selective therapeutic manipulation of Treg cells. In this review, we mainly summarize the heterogeneity of Treg cells and their potential therapeutic value in autoimmune diseases.