Dataset Information

CD69 prevents PLZF^hi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.

ABSTRACT: While CD69 may regulate thymocyte egress by inhibiting S1P₁ expression, CD69 expression is not thought to be required for normal thymocyte development. Here we show that CD69 is in fact specifically required for the differentiation of mature NKT2 cells, which do not themselves express CD69. Mechanistically, CD69 expression is required on CD24⁺ PLZF^hi innate precursors for their retention in the thymus and completion of their differentiation into mature NKT2 cells. By contrast, CD69-deficient CD24⁺ PLZF^hi innate precursors express S1P₁ and prematurely exit the thymus, while S1P₁ inhibitor treatment of CD69-deficient mice retains CD24⁺ PLZF^hi innate precursors in the thymus and restores NKT2 cell differentiation. Thus, CD69 prevents S1P₁ expression on CD24⁺ PLZF^hi innate precursor cells from aborting NKT2 differentiation in the thymus. This study reveals the importance of CD69 to prolong the thymic residency time of developing immature precursors for proper differentiation of a T cell subset.

SUBMITTER: Kimura MY

PROVIDER: S-EPMC6138739 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD69 prevents PLZFhi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.

Kimura Motoko Y MY Igi Akemi A Hayashizaki Koji K Mita Yukiyoshi Y Shinzawa Miho M Kadakia Tejas T Endo Yukihiro Y Ogawa Satomi S Yagi Ryoji R Motohashi Shinichiro S Singer Alfred A Nakayama Toshinori T

Nature communications 20180914 1

While CD69 may regulate thymocyte egress by inhibiting S1P1 expression, CD69 expression is not thought to be required for normal thymocyte development. Here we show that CD69 is in fact specifically required for the differentiation of mature NKT2 cells, which do not themselves express CD69. Mechanistically, CD69 expression is required on CD24+ PLZFhi innate precursors for their retention in the thymus and completion of their differentiation into mature NKT2 cells ...[more]

PMID: 30218105

Similar Datasets

Project description:Regulatory T cells (Tregs) are critical for generating and maintaining peripheral tolerance. Treg-based immunotherapy is valuable for the clinical management of diseases resulting from dysregulation of immune tolerance. However, the lack of potency is a potential limitation of Treg therapy. In addition, CD69 positive-Treg (CD69+ Treg) represent a newly identified subset of Tregs with potent immune suppressive capability. Methods: Foxp3 YFP-Cre CD69 fl/fl and CD4 Cre CD69 fl/fl mice were generated to determine the relevance of CD69 to Treg. Chromatin Immunoprecipitation Assay (ChIP) and luciferase Assay were performed to detect the regulation of CD69 transcription by heat shock transcription factor 1(HSF1). Gene expression was measured by western blotting and qRT-PCR. The differentiation of naive T cells to CD69+Foxp3+ iTregs was determined by flow cytometry. The immunosuppressive ability of Tregs was analyzed by ELISA and flow cytometry. Colon inflammation in mice was reflected by changes in body weight and colon length, the disease activity index (DAI), and H&E staining of colon tissues. Results: Induced Tregs (iTregs) from CD4 Cre CD69 fl/fl mice failed to alleviate colitis. The transcription factor HSF1 interacted with the promoter of the CD69 gene to prompt its transcription during Treg differentiation. Genetic and chemical inhibition of HSF1 impaired CD69+ Treg differentiation and promoted the pathogenesis of colitis in mice. In contrast, HSF1 protein stabilized by inhibiting its proteasomal degradation promoted CD69+ Treg differentiation and alleviated colitis in mice. Moreover, adoptive transfer of iTregs with HSF1 stabilization by proteasome inhibitor (PSI) dramatically prevented the development of colitis in mice and was accompanied by decreased production of pro-inflammatory cytokines and reduced accumulation of pro-inflammatory lymphocytes in colitis tissue, whereas Tregs induced in the absence of PSI were less stable and ineffective in suppressing colitis. Conclusions: HSF1 promotes CD69+ Tregs differentiation by activating the CD69 transcription, which is critical for the immunosuppressive function of Tregs. Stabilization of HSF1 by PSIs results in the efficient generation of Tregs with high potency to treat colitis and probably other autoimmune diseases involving Tregs deficiency.

Dataset Information

CD69 prevents PLZF^hi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.

Publications

CD69 prevents PLZF<sup>hi</sup> innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

CD69 prevents PLZFhi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.

Publications

CD69 prevents PLZF&lt;sup&gt;hi&lt;/sup&gt; innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CD69 prevents PLZF^hi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.

CD69 prevents PLZF<sup>hi</sup> innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.