Janus kinase 3-deficient T lymphocytes have an intrinsic defect in CCR7-mediated homing to peripheral lymphoid organs.
Chemokine-mediated signalling involves the activation of a Janus kinase (Jak) pathway. We have previously shown that Jak3 mediates CCR9 and CXCR4 signalling in response to CCL25 and CXCL12 in BM progenitors and thymocytes. The lack of peripheral lymph nodes and Peyer's patches observed in Jak3(-/-) mice suggested a possible role of Jak3 in CCR7-mediated homing to these organs. Here, we demonstrate phosphorylation of Jak3 in peripheral lymphocytes in response CCL19 and CCL21. In addition, Jak3(-/-) naïve T cells and pharmacologically inhibited Jak3(+/+) T lymphocytes have impaired chemotactic responses towards these ligands. Interestingly, CCR7 expression was higher in Jak3(-/-) thymocytes compared to their Jak3(+)(/-) littermates, indicating that the impaired migration must be caused by impaired CCR7-mediated signalling, in the absence of Jak3. In addition, adoptive transfer experiments showed that Jak3(+/+) mice reconstituted with Jak3(-/-) green fluorescent protein (GFP)(+) bone marrow progenitors had reduced T-lymphocyte homing to peripheral and mesenteric lymph nodes, compared to reconstitution with Jak3(+/+) GFP(+) progenitors. Furthermore, reciprocal transfer experiments indicated that Jak3(-/-) stromal cells were not responsible for the deficient T-cell homing. Finally, we performed direct competitive homing assays and demonstrated that Jak3(-/-) T lymphocytes have a clear defect in homing to peripheral and mesenteric lymph nodes, while migration to spleen was moderately impaired. Our data demonstrates that Jak3(-/-) T lymphocytes have an intrinsic defect in CCR7-mediated homing to peripheral lymphoid organs.
García-Zepeda
Eduardo A
EA
Departamento de Inmunología, Instituto de Investigaciones Biomédicas., Universidad Nacional Autónoma de México, México.
Licona-Limón
Ileana
I
Jiménez-Sólomon
M Fernanda
MF
Soldevila
Gloria
G
D000818:Animals; D002478:Cells, Cultured; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D053616:Janus Kinase 3 / Q000172:deficiency / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3