1. Academic Validation
  2. Cbl-b inhibited CD4+ T cell activation by regulating the expression of miR-99a/miR-125b

Cbl-b inhibited CD4+ T cell activation by regulating the expression of miR-99a/miR-125b

  • Int Immunopharmacol. 2023 Jan 10;115:109677. doi: 10.1016/j.intimp.2022.109677.
Mengyun Wu 1 Xiu Gao 1 Yuxu Tang 1 Wenyan Wu 1 Ji Zhou 1 Yu Shao 1 Chuangli Hao 2 Yi Yang 3 Jinping Zhang 4
Affiliations

Affiliations

  • 1 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, People's Republic of China.
  • 2 Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, People's Republic of China. Electronic address: hcl_md@163.com.
  • 3 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, People's Republic of China. Electronic address: yangyi87@suda.edu.cn.
  • 4 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, People's Republic of China. Electronic address: j_pzhang@suda.edu.cn.
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.

Keywords

Cbl-b; HOXA10; SHP-2; T cell activation; miRNA.

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