Impaired chemokine‐induced migration during T‐cell development in the absence of Jak 3

Abstract

SUMMARYThe arrival of bone marrow T-cell progenitors to the thymus, and the directed migration of thymocytes, are thought to be regulated by the expression of chemokines and their receptors. Recent data has shown that the Jak ⁄Stat signalling pathway is involved in chemokine receptor signalling. We have investigated the role of Jak 3 in chemokine-mediated signalling in the thymus using Jak 3 -⁄ -mice. These mice show defects in T-cell development, as well as in peripheral T-cell function, resulting in a hypoplastic thymus and an altered T-cell homeostasis. Here we demonstrate, for the first time, that bone marrow progenitors and thymocytes from Jak 3 -⁄ -mice have decreased chemotactic responses to CXCL12 and CCL25. We also show that Jak 3 is involved in signalling through CCR9 and CXCR4, and that specific inhibition of Jak 3 in wild-type progenitors and thymocytes decreases their chemotactic responses towards CCL25 and CXCL12. Finally, quantitative reverse transcription-polymerase chain reaction analysis showed that thymocytes from Jak 3 -⁄ -mice express similar levels of CXCR4 and CCR9 compared to wild-type mice. Altogether, deficient CCL25-and CXCL12-induced migration could result in a homing defect of T-cell progenitors to the thymus, as well as in a deficient thymocyte migration through the thymic stroma. Our results strongly suggest that the absence of Jak 3 affects T-cell development, not only through an impaired interleukin-7 receptor (IL-7R)-mediated signalling, but also through impaired chemokine-mediated responses, which are crucial for thymocyte migration and differentiation.

CXCL12 Signaling Is Independent of Jak2 and Jak3

“…CXCR4 Signaling Is Not Affected by Jak2 and Jak3 in HEK293 Cells-Using an inhibitor that blocks both Jaks as well as other kinases, previous studies have concluded that Jaks are essential for chemokine signaling (18,20,22,27,28). However, the use of pharmacologic inhibitors may lead to erroneous conclusions and therefore need to be verified by genetic approaches.…”

“…A recent study that examined CXCL12 signaling in murine Jak3-deficient thymocytes concluded that chemotaxis is impaired (27). The authors also concluded that CXCR4 expression was normal at the level of mRNA.…”

“…Importantly, it has also been concluded that Jaks are an essential aspect of chemokine signaling. Jak2 and Jak3 were reported to associate with and phosphorylate CXCR4, and putatively selective Jak inhibitors block CXCL12 signaling, as measured by inhibition of substrate phosphorylation, calcium mobilization, and cell migration (18,27). Unfortunately, these inhibitors are not selective for Jaks (28).…”

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

“…G-protein dependent activation of CXCR4 also induces several MAPKs signaling pathways such as ERK, JNK and P38 (Bajetto A et al, 2001;Han Y et al, 2001a;Han Y et al, 2001b;Fernandis AZ et al, 2004;Alvarez S et al, 2005). In addition, CXCL12/CXCR4 activates the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in a PTX independent manner (Vila- Coro AJ et al, 1999;Soriano SF et al, 2003;Soldevila G et al, 2004). CXCL12/CXCR4 signaling is regulated by G protein-coupled receptor kinases (GRKs) and β-arrestins (Fig.…”

Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas

“…ELAVL1 codes for a RNA-binding factor expressed in a wide variety of cells and involved in RNA degradation (King et al, 2000). CCL25 encodes for a chemokine molecule (Soldevila et al, 2004). ANGPL4 codes for a factor promoting angiogenesis and is overexpressed in several tumours (Tait and Jones, 2004).…”