ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/029/SRR18338829/SRR18338829.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/021/SRR18338821/SRR18338821.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/032/SRR18338832/SRR18338832.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/026/SRR18338826/SRR18338826.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/038/SRR18338838/SRR18338838.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/015/SRR18338815/SRR18338815.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/030/SRR18338830/SRR18338830.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/027/SRR18338827/SRR18338827.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/033/SRR18338833/SRR18338833.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/037/SRR18338837/SRR18338837.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/016/SRR18338816/SRR18338816.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/020/SRR18338820/SRR18338820.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/022/SRR18338822/SRR18338822.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/024/SRR18338824/SRR18338824.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/018/SRR18338818/SRR18338818.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/035/SRR18338835/SRR18338835.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/025/SRR18338825/SRR18338825.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/036/SRR18338836/SRR18338836.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/028/SRR18338828/SRR18338828.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/031/SRR18338831/SRR18338831.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/023/SRR18338823/SRR18338823.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/017/SRR18338817/SRR18338817.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/019/SRR18338819/SRR18338819.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/034/SRR18338834/SRR18338834.fastq.gzprimary200OKGenomicsBenaroya Research Institutehttps://www.ebi.ac.uk/ena/browser/view/PRJNA816921Homo sapiensCbl-b is a negative regulator of T cell activation and in murine models a lack of CBLB results in resistance of T effectors to Tregs, a feature of T cells in many autoimmune diseases. Here, we used trackable gene-editing approaches to knock out CBLB in primary human CD4+ T cells. We found that CBLB-KO CD4+ T cells were hyper-proliferative and produced excess amounts of IL-2 at baseline and upon TCR stimulation. CBLB-KO CD4+ T cells were resistant to Treg suppression in vitro, which was partially reversed by blockade of IL-2. RNAseq and puromycin incorporation assays demonstrate that CBLB-KO CD4+ T cells can overcome Treg suppression on the transcriptional and translational level resulting in the overproduction of cytokines to drive the proliferation and activation of Teffs. These findings also highlight a potential mechanism of Teff resistance in human autoimmune disease and the power of gene editing of primary T cells to explore disease mechanisms. Overall design: 24 samples total. 4 donors, 2 treatments (CBLB-KO or AAVS1-KO), 3 stimulations (none, CD3CD28 beads, CD3CD28 beads + Treg exposure)ENAfalseDissecting the role of CBLB in human T cell activation and suppressionDissecting the role of CBLB in human T cell activation and suppression2025-09-172022-07-21PRJNA816921GSE1988109606