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Increasing evidence suggests that mucosal-associated invariant T cells (MAITs) play a crucial role in anti-tumor responses against various cancers. In this study, we investigated the immune characteristics of MAIT cells in patients with acute myeloid leukemia (AML). Using multi-parameter flow cytometry, we performed phenotypic and functional analysis of MAITs in peripheral blood or bone marrow samples collected from 131 patients with AML including 99 newly diagnosed, 18 remission, and 14 relapsed cases, as well as 69 healthy controls. We found that MAITs exhibit signs of aging and exhaustion, particularly in CD8+ MAITs subset, at newly diagnosis. MAITs exhibit an effector memory or terminally differentiated phenotype. Frequency and number of MAITs reflect AML cell genetic features, tumor burden, disease status, and treatment responsiveness. Moreover, MAITs exhibit a highly activated or even exhausted state, as indicated by upregulation of PD-1. Furthermore, impaired production of Th1-type cytokines and increased secretion of Th17-type cytokines, granzyme B, and perforin were observed in MAITs from AML patients. Additionally, MAITs shifted toward producing cytokines that promote tumor progression, such as IL-8. Lower frequency of MAITs was associated with poorer overall survival (OS), and multivariate analysis revealed that MAITs frequency < 2.12% was an independent prognostic factor affecting OS. Collectively, our findings suggest that MAITs may play a role in immune deficiency in AML, emphasizing their potential importance in AML pathogenesis and treatment. These discoveries provide a theoretical basis for the development of novel immunotherapeutic strategies in AML. [ABSTRACT FROM AUTHOR]

Objective. The current study sought to compare the effects of the addition of Qingshen granules to conventional Western medicine on immune function in patients with comorbid chronic renal failure and damp-heat syndrome and to explore the possible mechanisms responsible for any differences observed. Methods. Through a multicenter, randomized, controlled study, a total of 282 eligible patients were divided into experimental (n = 136) and control groups (n = 146). All of the patients were treated with conventional Western medical therapy. The experimental group also received Qingshen granules three times daily for 12 weeks. Clinical efficacy was observed in the two groups. Peripheral blood levels of CD4+ T cells, CD8+ T cells, Th17 cells, nuclear factor-κB p65 (NF-κB p65) activity, serum interleukin-17 (IL-17), serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), tumor necrosis factor receptor-associated factor 6 (TRAF6), fibronectin (FN), and type IV collagen (Col-IV) were detected in both groups. Results. The total clinical curative effective rate was significantly higher p < 0.05 in the experimental group (79.41%) than in the control group (67.12%). Before treatment, there were no significant differences in CD4+/CD8+ T cell ratio, Th17 cell level, NF-κB p65 activity, serum IL-17, IL-6, TNF-α, TRAF6, FN, and Col-IV between the experimental and control groups p > 0.05 ; however, all of the measures were significantly higher than those observed in a healthy comparison group (p < 0.05 or p < 0.01). After treatment, the above indexes in the experimental group were significantly lower than those before treatment (p < 0.05 or p < 0.01). Similarly, NF-κB p65 activity, serum IL-17, TNF-α, TRAF6, FN, and Col-IV in the control group were significantly lower than the levels observed prior to treatment (p < 0.05 or p < 0.01); however, while all of the other indexes were lower than those observed before treatment, the differences were not statistically significant p > 0.05 . Conclusion. Qingshen granules adjust immune dysfunction, improve immunity mediated inflammatory response, and attenuate renal fibrosis in patients with comorbid chronic renal failure and damp-heat syndrome. [ABSTRACT FROM AUTHOR]

Background: This study is aimed at exploring the role of B7-H4 in the pathogenesis of primary Sjögren's syndrome (pSS) in NOD/Ltj mouse.Methods: B7-H4 expression in salivary glands was examined by IHC, and lymphocyte infiltration was showed by H&E. Next, anti-B7-H4 mAb or immunoglobulin isotype was injected into NOD/Ltj mice. Cytokine levels were measured by quantitative RT-PCR, and immunoglobulins were measured by ELISA. T cell subsets were analyzed by flow cytometry. Last, we treated NOD/Ltj mice with B7-H4Ig and control Ig. CD4+Foxp3+ T cells were assessed by immunohistochemistry. Two-tailed Student's t-tests were used to detect the statistical difference in various measures between the two groups.Results: B7-H4 expression was remarkably reduced in salivary glands of NOD/Ltj mice at 15 weeks compared with the NOD/Ltj mice at 8 weeks. Anti-B7-H4 mAb treatment increased lymphocyte infiltration in salivary glands. Inflammatory cytokines including IL-12, IL-18, IL-1α, TNF-α, IFN-α, and BAFF were upregulated markedly in anti-B7-H4 mAb-treated mice compared to IgG isotype-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb-treated mice had lower levels of CD4+Foxp3+/CD4+ T cells in spleen. Moreover, Foxp3 mRNA levels of salivary glands were diminished in anti-B7-H4 mAb-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb inhibited CD4+Foxp3+/CD4+ T cell production, while B7-H4Ig would promote naïve CD4+ T into Treg differentiation. Administration with B7-H4Ig displayed significantly decreased lymphocyte infiltration in salivary glands and low levels of total IgM and IgG in serum. Analysis of inflammatory cytokines in salivary glands after B7-H4Ig treatment revealed that the mRNA levels of IL-12, IL-6, IL-18, IL-1α, TNF-α, and IFN-α were significantly downregulated in B7-H4Ig-treated mice compared to control Ig treatment. B7-H4Ig-treated mice had significantly higher levels of CD4+Foxp3+/CD4+ T cells in spleen. IHC in salivary gland revealed that CD4+Foxp3+ T cells of B7-H4Ig treatment mouse were more than control Ig treatment.Conclusions: Our findings implicate that B7-H4 has a protective role for salivary gland epithelial cells (SGECs) and therapeutic potential in the treatment of pSS. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs. Methods To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN. Results Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103− DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice. Conclusion Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD. [ABSTRACT FROM AUTHOR]

Objectives: To explore the immunological abnormalities in patients with primary immune thrombocytopenia (ITP), and analyze its relationship with treatment. Methods: Proportion of different immune cell subsets were detected in the peripheral blood of 124 ITP patients at different time points and 45 normal controls by flow cytometry. The treatments included glucocorticoids, intravenous IgG as first-line treatment and second-line drugs. Results: Elevated CD4/CD8 ratio and decreased the proportion of NK and CD4 + CD25 + CD127low regulatory T cells (Tregs) were found in pre-treated ITP patients than healthy controls. The newly diagnosed group had a significantly higher CD4/CD8 ratio than the relapsed group, but no differences in the proportion of B cells, NK cells and Tregs. No relationships were found between the curative effect and the pre-treated cell subsets within both the effective and ineffective groups. Furthermore, compared with the ineffective group, the effective group had higher Tregs and lower CD4/CD8 ratio post-treatment, but no significant differences in NK and B cells. Conclusion: ITP patients presented with a high CD4/CD8 ratio and low levels of Tregs and NK cells, suggesting that immune deregulation was involved in the pathogenesis of ITP. The pretreated immune status of ITP patients may not be related to the curative effect. Tregs significantly increased in the effective group post-treatment, highlighting that the mechanism of restoring Tregs may be involved in the treatment of ITP. However, whether or not the targeted regulation of Tregs is an effective treatment for ITP still requires further studies. [ABSTRACT FROM AUTHOR]

Aim Our previous study confirmed the defect of B7-H4 expression in peripheral blood and salivary glands of patients with primary Sjögren's syndrome ( pSS). The aim of this study was to analyze the effect of the deficit expression of B7-H4 on CD4+ T cells. Methods CD4+ T cells were purified by magnetic-activated cell sorting MACS. The proliferation and cytokine production of CD4+ T cells co-cultured with purified salivary gland epithelial cells ( SGECs) from pSS or non- SS sicca syndrome were detected. Results By co-culturing the gland cells with CD4+ T cells, we found the proliferation of CD4+ T cells was significantly suppressed. The effect was weaker when SGECs from pSS patients were used compared to that from non- pSS sicca syndrome controls. Simultaneously, the productions of cytokines interleukin ( IL)-5, IL-13, IL-17A, IL-6 in supernatant were reduced and also SGECs from pSS patients decreased them less than that from non- SS controls. Conclusions The decrease of B7-H4 expression in salivary glands of SS patients contributes to the defect of negatively regulating the inflammation caused by CD4+ T cells, thereby providing new insights into the role of B7-H4 in the inflammatory process of salivary glands in SS. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) have been recognized as having a major role in maintaining peripheral tolerance and preventing and limiting autoimmune and chronic inflammatory diseases. Tregs derive from the thymus and also develop peripherally. In this review, we discuss recent progress in our understanding of the basic mechanisms involved in Treg development and function in protecting against autoimmunity in the periphery, including thymic selection, peripheral induction and the many mechanisms of Treg suppression. Specifically in kidney disease, Tregs have been shown to play a role in limiting injury and may potentially have a therapeutic role. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) play an essential role in sustaining self-tolerance and immune homeostasis. Despite many studies on the correlation between Tregs accumulation and age, or malignancies, the related mechanism hasn’t been well explored. To find out the mechanism of Tregs accumulation in aged urinary bladder cancer, we examined the novel cellular senesence gene SENEX and relevant apoptosis gene mRNA expression in sorted CD4+CD25hi Tregs from aged UBC donors, evaluated serum cytokine profiles related to tumor immunopathology, and further explored the relationship between SENEX expression, apoptosis gene expression and cytokine secretion. After having silenced down SENEX gene expression with RNA interference, we also evaluated the cellular apoptosis of Tregs sorted from aged UBC patients in response to H2O2-mediated stress. Our data indicated that upregulated SENEX mRNA expression in Tregs of aged UBC patients was correlated with pro-apoptotic gene expression and cytokine concentration. Silencing SENEX gene expression increased cellular apoptosis and pro-apoptotic gene expression of Tregs, in response to H2O2-mediated stress. Upregulated SENEX mRNA expression together with decreased pro-apoptotic gene expression and disturbances in cytokines synthesis may contribute to the Tregs proliferation and promote tumorigenesis and metastasis. Overall, upregulation of cellular senescence gene SENEX, was associated to regulatory T cells accumulation in aged urinary bladder cancer. Our study provides a new insight into understanding of peripheral Tregs accumulation in aged malignancies. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease continues to be a major life-threatening complication after allogeneic hematopoietic stem cells transplantation (aHSCT). The relationship of acute GVHD (aGVHD) with the levels of peripheral CD4+CD25high T cells in patients after aHSCT and in their corresponding donors is not fully investigated. We examined the levels of CD4+CD25high T cells in patients after aHSCT and in their corresponding donors, and analyzed the relationship of CD4+CD25high T cells to the incidence and prognosis of aGVHD. The recipients with normal or high CD4+CD25high T cells (three of eight, 37.5%) had no or mild aGVHD (grade I), and all survived during the follow-up period. In striking contrast, the recipients with lower or no CD4+CD25high T cells suffered from greater than grade II aGVHD (four of four, 100%), and all died within 1-year post-aHSCT. Moreover, the number of CD4+CD25high T cells in recipients correlated significantly with that of their corresponding donors. The CD4+CD25high T cells from the recipients and their corresponding donors expressed high levels of Foxp3, and effectively suppressed the proliferation of CD4+CD25− responder T cells. This study suggests that human Treg cells may play an important role in aGVHD, as has been seen in murine models. The levels of peripheral CD4+CD25high T cells in recipients and donors could be helpful for predicting of the onset and outcome of aGVHD. [ABSTRACT FROM AUTHOR]

Presents the abstract 'Reconstitution of CD4+ T Cells Reduces Renal Injury in Scid Mice With Adriamycin Nephropathy,' by Yiping Wang, Lukas Kairaitis, Yuet-Ching Tay, Yang Wang, Ling Zheng and David C.H. Harris.

The CD40-CD154 costimulatory pathway has been shown to be critical for both T- and B-cell activation in autoimmune disease. Here, we assessed the effects of blocking this pathway using CD40 DNA vaccine enhanced by dendritic cell targeting on the development of active Heymann nephritis, a rat model of human membranous nephropathy. DNA vaccination delivers plasmid DNA encoding the target antigen, either alone or in combination with enhancing elements, to induce both humoral and cellular immune responses. To determine whether CD40 DNA vaccine targeting the encoded CD40 directly to dendritic cells would improve the efficacy of the vaccination against self-protein CD40, we utilized a plasmid encoding a single-chain Fv antibody specific for the dendritic cell-restricted antigen-uptake receptor DEC205 (scDEC), the target gene CD40, and the adjuvant tetanus sequence p30. This vaccine plasmid was compared to a control plasmid without scDEC. Rats vaccinated with scDEC-CD40 had significantly less proteinuria and renal injury than did rats receiving scControl-CD40 and were protected from developing Heymann nephritis. Thus, CD40 DNA vaccination targeted to dendritic cells limits the development of Heymann nephritis. [ABSTRACT FROM AUTHOR]

The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues. [Display omitted] • Loss of CD58 expression confers immune evasion through multiple mechanisms • CD58 and PD-L1 are co-regulated in cancer cells • Genome-scale screens identify CMTM6 as important regulator of CD58 • CD58 and PD-L1 compete for CMTM6 for protein stability Ho et al. identify a critical role for defects in the CD58-CD2 axis as drivers of immune evasion and impaired intratumoral T cell infiltration. CD58 and PD-L1 compete for CMTM6 for protein stabilization, thus representing an additional mechanism for balancing immune-stimulatory and -inhibitory signals. [ABSTRACT FROM AUTHOR]

Previous studies found cDC1s to be protective in early stage anti-GBM disease through Tregs, but pathogenic in late stage Adriamycin nephropathy through CD8+ T cells. Flt3 ligand is a growth factor essential for cDC1 development and Flt3 inhibitors are currently used for cancer treatment. We conducted this study to clarify the role and mechanisms of effects of cDC1s at different time points in anti-GBM disease. In addition, we aimed to utilize drug repurposing of Flt3 inhibitors to target cDC1s as a treatment of anti-GBM disease. We found that in human anti-GBM disease, the number of cDC1s increased significantly, proportionally more than cDC2s. The number of CD8+ T cells also increased significantly and their number correlated with cDC1 number. In XCR1-DTR mice, late (day 12–21) but not early (day 3–12) depletion of cDC1s attenuated kidney injury in mice with anti-GBM disease. cDC1s separated from kidneys of anti-GBM disease mice were found to have a pro-inflammatory phenotype (i.e. express high level of IL-6, IL-12 and IL-23) in late but not early stage. In the late depletion model, the number of CD8+ T cells was also reduced, but not Tregs. CD8+ T cells separated from kidneys of anti-GBM disease mice expressed high levels of cytotoxic molecules (granzyme B and perforin) and inflammatory cytokines (TNF-α and IFN-γ), and their expression reduced significantly after cDC1 depletion with diphtheria toxin. These findings were reproduced using a Flt3 inhibitor in wild type mice. Therefore, cDC1s are pathogenic in anti-GBM disease through activation of CD8+ T cells. Flt3 inhibition successfully attenuated kidney injury through depletion of cDC1s. Repurposing Flt3 inhibitors has potential as a novel therapeutic strategy for anti-GBM disease. • cDC1s are pathogenic in anti-GBM disease through activating CD8+ T cells. • Flt3 inhibitor depleted cDC1s selectively, resulting in attenuation of kidney injury. • Flt3 inhibition is a novel therapy for anti-GBM disease, with accelerated translational potential through drug repurposing. [ABSTRACT FROM AUTHOR]

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration. [Display omitted] • Single-cell/spatial transcriptomics atlas of melanoma brain and extracranial metastases • Chromosomal instability is associated with brain metastasis • Cancer cells in brain metastases enrich for a neuronal-like metaprogram • Macrophages have a pro-tumorigenic phenotype in brain metastases Multi-modal single-cell analysis reveals genomic, transcriptional, and tumor-microenvironmental features of treatment-naive human melanoma brain metastases compared with extracranial metastases. [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cells play important roles in inducing immune tolerance, preventing allograft rejection, and regulating immune responses in both autoimmune disease and graft-versus-host disease. In order to evaluate a possible protective effect of plasmacytoid dendritic cells against renal inflammation and injury, we purified these cells from mouse spleens and adoptively transferred lipopolysaccharide (LPS)-treated cells, modified ex vivo, into mice with adriamycin nephropathy. These LPS-treated cells localized to the kidney cortex and the lymph nodes draining the kidney, and protected the kidney from injury during adriamycin nephropathy. Glomerulosclerosis, tubular atrophy, interstitial expansion, proteinuria, and creatinine clearance were significantly reduced in mice with adriamycin nephropathy subsequently treated with LPS-activated plasmacytoid dendritic cells as compared to the kidney injury in mice given naive plasmacytoid dendritic cells. In addition, LPS-pretreated cells, but not naive plasmacytoid dendritic cells, convert CD4+CD25− T cells into Foxp3+ regulatory T cells and suppress the proinflammatory cytokine production of endogenous renal macrophages. This may explain their ability to protect against renal injury in adriamycin nephropathy. [ABSTRACT FROM AUTHOR]

Abstract: Graft-versus-host disease (GVHD) is a frequent and life threatening complication of allogeneic haematogenesis stem cell transplantation (aHSCT). The correlation of CD4+CD25+ regulatory T cells (Tregs) in the patients after aHSCT to the occurrence and severity of acute and chronic GVHD (aGVHD and cGVHD) is not fully investigated. Here, we examined the levels of CD4+CD25+ Tregs by assessment of CD4+CD25high and CD4+CD25+CD127low in peripheral blood, and the levels of serum TGF-β and TNF-α in 56 patients at early immune reconstitution following aHSCT. Our data showed a significant reduction in the frequency of Tregs in patients with grades II–IV aGVHD and extensive cGVHD compared to healthy controls. Moreover, a decreased level of CD4+CD25+ Tregs was correlated to increased severity of GVHD. The levels of CD4+CD25+ Tregs in non-GVHD groups were however significantly higher than that in healthy controls. A significant decrease in the levels of TGF-β and a significant increase the levels of TNF-α was also seen with increased severity of GVHD. This study suggested that measurement of CD4+CD25+ Tregs along with serum TGF-β and TNF-α at early immune reconstruction after aHSCT may indicate the onset and severity of both aGVHD and cGVHD. [ABSTRACT FROM AUTHOR]