Abstract
The molecular regulation of T cell activation has always been a hot topic in immunology. It has been reported that Cbl-b inhibits T cell activation, but the specific molecular mechanism especially for transcriptional regulation has not been very clear so far. Our present study showed that ablation of Cbl-b resulted in the increased expression of miR-99a and miR-125b, and the antagonism of miR-99a or miR-125b could inhibit the Cbl-b-/- T cell over-activation partly. Further study demonstrated that Cbl-b could bind and ubiquitinate SHP-2 in the activated T cells. The activation of SHP-2 deficient T cells was significantly inhibited. Western blot showed that SHP-2 could dephosphorylate HOXA10, and HOXA10 could enter the nucleus under the stimulation of anti-CD3 antibody alone in Cbl-b deficient T cells. Luciferase reporter assay and CUT&Tag qPCR showed that HOXA10 could regulate the expression of miR-99a/miR-125b. Real-time PCR and western blot further indicated that miR-99a/miR-125b functioned on PI3K/AKT pathway to regulate T cell activation. In conclusion, our study demonstrated that Cbl-b ubiquitinated SHP-2 to arrest HOXA10-mediated CD4+ T cell activation by regulating the expression of miR-99a/miR-125b and their function on PI3K/AKT pathway, which might providing a new explanation for the regulation of T cell activation and potential new idea for autoimmune diseases and tumor immunotherapies.