RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

Abstract

T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation.

Sumoylation of RORγt regulates TH17 differentiation and thymocyte development

“…However, we identified several genes, including Rasgrp1 , Ets2, Cd6 , Ptcra , Rasgrp4 , and Cd4 , that were downregulated in RORγt K31R/K31R thymocytes compared to WT thymocytes (Fig. 6h , genes listed on the right in red) and are known to regulate thymocyte development 35 – 38 . We found that the CD4 − encoding Cd4 gene was downregulated in RORγt K31R / K31R thymocytes compared to WT thymocytes (Fig.…”

Different populations of CD11b+ dendritic cells drive Th2 responses in the small intestine and colon

“…Rasgrp3 is upregulated, whereas H2-Eb2 and Il1f9 are downregulated upon SEA incubation in both populations. RAS activators, such as RasGRP3, provide a key link between cell surface receptors and RAS activation, and RasGRP3 has been shown to control CCR9-dependent entry of early thymic progenitors in the thymus45, B-cell receptor signalling46 and the production of Toll-like receptor (TLR)-triggered proinflammatory cytokines in macrophages47. Together with the downregulation of H2-Eb2 and Il1f9 , a dampening of proinflammatory responses is thus observed in these SEA-cultured DCs.…”

CCL25/CCR9 interaction promotes the malignant behavior of salivary adenoid cystic carcinoma via the PI3K/AKT signaling pathway

“…In addition, the JAK/STAT pathway activated by CCL25 can alleviate the antitumor ability of T cells and promote the immune escape of tumor cells ( Soldevila et al, 2004 ; Tu et al, 2016 ). CCR9/CCL25 can also activate Ras/Raf/MARK and RhoA/Rock signals to strengthen the degradation of ECM and change the cytoskeleton arrangement, thus enhancing tumor cell motility ( Golec, Henao Caviedes & Baldwin, 2016 ). Our results showed that the interaction of CCL25 and CCR9 could significantly upregulate the S473 phosphorylation level of AKT in SACC cells, indicating that AKT was activated.…”