Cbl-b is a negative regulator of T cell activation, and in murine models, a lack of Cblb results in resistance of T effector (Teff) cells to T regulatory (Treg) cells, 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-knockout (CBLB-KO) CD4+ T cells were hyperproliferative and produced excessive amounts of IL-2. CBLB-KO CD4+ T cells were resistant to Treg suppression in vitro, which was partially reversed by blockade of IL-2. RNA-sequencing and puromycin incorporation assays demonstrated that CBLB-KO CD4+ T cells can overcome Treg suppression on the transcriptional and translational levels, resulting in the overproduction of cytokines to drive the proliferation and activation of Teff cells. These findings highlight a potential mechanism of Teff resistance in human autoimmune disease and the power of gene editing primary T cells to explore disease mechanisms.

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