WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which was shown to correlate with ETV6-RUNX1 translocation and favorable prognosis in childhood leukemia. It has a broad expression pattern in hematopoietic and non-hematopoietic cells. Our previous work described WBP1L as a regulator of CXCR4 signaling and hematopoiesis. Here, we show that hematopoiesis in the mice with Wbp1l germline deletion is dysregulated, already at the level of hematopoietic stem cells and early progenitors. We further demonstrate that thymi of WBP1L-deficient mice are significantly enlarged and contain increased numbers of thymocytes of all subsets. This can potentially be explained by increased generation of multipotent progenitors 4 (MPP4) in the bone marrow, from which the thymus-seeding progenitors are derived. We also observed increases in multiple cell types in the blood. In addition, we show that WBP1L regulates hematopoietic stem cell functionality and leukocyte progenitor proliferation and gene expression during hematopoietic stem and progenitor cell transplantation, which contribute to more efficient engraftment of WBP1L-deficient cells. WBP1L thus emerges as a regulator of hematopoietic stem and progenitor cell function, which controls leukocyte numbers at the steady state and after bone marrow transplantation.

• Klíčová slova
• T cell development, WBP1L, hematopoiesis, hematopoietic stem and progenitor cell transplantation, hematopoietic stem cells, transmembrane adaptor protein,
• MeSH
• hematopoetické kmenové buňky * fyziologie   MeSH
• hematopoéza * MeSH
• membránové proteiny * genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• počet leukocytů MeSH
• regulace genové exprese MeSH
• thymocyty fyziologie   MeSH
• thymus * cytologie   fyziologie   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové proteiny * MeSH
• Wbp1l protein, mouse MeSH Prohlížeč

The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14+Sirpα+ population of monocyte-derived dendritic cells (CD14+moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14+moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25+Foxp3+ Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14+moDC, the generation of Tregs, and thereby the establishment of central tolerance.

• MeSH
• analýza jednotlivých buněk MeSH
• autoantigeny imunologie   MeSH
• autotolerance MeSH
• chemokiny imunologie   metabolismus   MeSH
• dendritické buňky imunologie   MeSH
• epitelové buňky imunologie   metabolismus   MeSH
• kolitida imunologie   MeSH
• lipopolysacharidové receptory metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• převzatá imunita MeSH
• prezentace antigenu MeSH
• průtoková cytometrie MeSH
• receptory imunologické metabolismus   MeSH
• regulační T-lymfocyty imunologie   transplantace   MeSH
• sekvenční analýza RNA MeSH
• separace buněk MeSH
• signální transdukce imunologie   MeSH
• thymus cytologie   imunologie   MeSH
• toll-like receptory metabolismus   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoantigeny MeSH
• Cd14 protein, mouse MeSH Prohlížeč
• chemokiny MeSH
• lipopolysacharidové receptory MeSH
• receptory imunologické MeSH
• Sirpa protein, mouse MeSH Prohlížeč
• toll-like receptory MeSH