CLEC-2 is required for development and maintenance of lymph nodes

• Published in: Blood 2014-05, Vol.123 (20), p.3200-3207
• Main Authors: Bénézech, Cécile, Nayar, Saba, Finney, Brenda A., Withers, David R., Lowe, Kate, Desanti, Guillaume E., Marriott, Clare L., Watson, Steve P., Caamaño, Jorge H., Buckley, Christopher D., Barone, Francesca
• Format: Article
• Language: English
• Subjects: Animals; Blood Platelets - metabolism; Cell Proliferation; Cells, Cultured; Endothelium, Lymphatic - cytology; Endothelium, Lymphatic - metabolism; Gene Deletion; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Lymph Nodes - cytology; Lymph Nodes - growth & development; Lymph Nodes - metabolism; Lymphangiogenesis; Megakaryocytes - metabolism; Mice; Mice, Inbred C57BL; Vascular Biology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-03-489286

The importance of CLEC-2, a natural ligand/receptor for Gp38/Podoplanin, in the formation of the lymphatic vasculature has recently been demonstrated. As the development and maintenance of lymph nodes (LNs) is dependent on the formation of the lymphatic vasculature and the differentiation of Gp38/Podoplanin+ stromal cells, we investigated the role of CLEC-2 in lymphoneogenesis and LN homeostasis. Using constitutive Clec1b−/− mice, we showed that while CLEC-2 was not necessary for initiation of the LN anlage, it was required at late stages of development. Constitutive deletion of CLEC-2 induced a profound defect in lymphatic endothelial cell proliferation, resulting in lack of LNs at birth. In contrast, conditional deletion of CLEC-2 in the megakaryocyte/platelet lineage in Clec1bfl/flPF4-Cre mice led to the development of blood-filled LNs and fibrosis, in absence of a proliferative defect of the lymphatic endothelial compartment. This phenotype was also observed in chimeric mice reconstituted with Clec1bfl/flPF4-Cre bone marrow, indicating that CLEC-2 expression in platelets was required for LN integrity. We demonstrated that LNs of Clec1bfl/flPF4-Cre mice are able to sustain primary immune responses but show a defect in immune cell recirculation after repeated immunizations, thus suggesting CLEC-2 as target in chronic immune response. •CLEC-2 is necessary for lymphatic cell proliferation and lymph node anlage persistence after birth.•Lack of CLEC-2 expression on megakaryocytes and platelets compromises lymph node integrity in adult life.