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Cell therapy is promising for heart failure treatment, with growing interest in cardiovascular progenitor cells (CPCs) from pluripotent stem cells. A major challenge is managing the immune response, due to their allogeneic source. Regulatory T cells (Treg) offer an alternative to pharmacological immunosuppression by inducing immune tolerance. This study assesses whether Treg therapy can mitigate the xeno-immune response, improving cardiac outcomes in a mouse model of human CPC intramyocardial transplantation. CPCs stimulated immune responses in allogeneic and xenogeneic settings, causing proliferation in T cell subsets. Tregs showed immunosuppressive effects on T lymphocyte populations when co-cultured with CPCs. Post infarction, CPCs were transplanted intramyocardially into an immune-competent mouse model 3 weeks after myocardial infarction. Human or murine Tregs were intravenously administered on transplantation day and three days later. Control groups received CPCs without Tregs or saline (PBS). CPCs with Tregs improved LV systolic function in three weeks, linked to reduced myocardial fibrosis and enhanced angiogenesis. This was accompanied by decreased splenocyte NK cell populations and pro-inflammatory cytokine levels in cardiac tissue. Treg therapy with CPC transplantation enhances cardiac functional and structural outcomes in mice. Though it does not directly avert graft rejection, it primarily affects NKG2D+ cytotoxic cells, indicating systemic immune modulation and remote heart repair benefits.

Innate antiviral factors are essential for effective defense against viral pathogens. However, the identity of major restriction mechanisms remains elusive. Current approaches to discover antiviral factors usually focus on the initial steps of viral replication and are limited to a single round of infection. Here, we engineered libraries of >1500 replication-competent HIV-1 constructs each expressing a single gRNAs to target >500 cellular genes for virus-driven discovery of antiviral factors. Passaging in CD4+ T cells robustly enriched HIV-1 encoding sgRNAs against GRN, CIITA, EHMT2, CEACAM3, CC2D1B and RHOA by >50-fold. Using an HIV-1 library lacking the accessory nef gene, we identified IFI16 as a Nef target. Functional analyses in cell lines and primary CD4+ T cells support that the HIV-driven CRISPR screen identified restriction factors targeting virus entry, transcription, release and infectivity. Our HIV-guided CRISPR technique enables sensitive discovery of physiologically relevant cellular defense factors throughout the entire viral replication cycle. Innate immune mechanisms are critical for antiviral defense. Here, the authors developed a CRISPR/Cas9-based HIV-driven approach to identify cellular factors compromising viral transcription, assembly, release or infectivity in human T cells. They identify targets of the Nef protein as antiviral factors.

Mycobacterium tuberculosis ( Mtb ), the causative agent of tuberculosis (TB), is the most common coinfection among people living with HIV-1. This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the impact of the HIV-1/TB coinfection on HIV-1 replication and latency in CD4 + T cells remains poorly studied. Using the acellular fraction of tuberculous pleural effusion (TB-PE), we investigated whether viral replication and HIV-1 latency in CD4 + T cells are affected by a TB-associated microenvironment. Our results revealed that TB-PE impaired T cell receptor-dependent cell activation and decreased HIV-1 replication in CD4 + T cells. Moreover, this immunosuppressive TB microenvironment promoted viral latency and inhibited HIV-1 reactivation. This study indicates that the TB-induced immune response may contribute to the persistence of the viral reservoir by silencing HIV-1 expression, allowing the virus to persist undetected by the immune system, and increasing the size of the latent HIV-1 reservoir. Subject areas: Immunology, Virology