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* Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan; and
School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
Certain lymphoid chemokines are selectively and constitutively expressed in the high endothelial venules (HEV) of lymph nodes and Peyer’s patches, where they play critical roles in the directional migration of extravasating lymphocytes into the lymphoid tissue parenchyma. How these chemokines are selectively localized and act in situ, however, remains unclear. In the present study, we examined the possibility that basal lamina-associated extracellular matrix proteins in the HEVs are responsible for retaining the lymphoid chemokines locally. Here we show that collagen IV (Col IV) bound certain lymphoid chemokines, including CCL21, CXCL13, and CXCL12, more potently than did fibronectin or laminin-1, but it bound CCL19 and CCL5 only weakly, if at all. Surface plasmon resonance analysis indicated that Col IV bound CCL21 with a low nanomolar KD, which required the C-terminal region of CCL21. Col IV can apparently hold these chemokines in their active form upon binding, because the Col IV-bound chemokines induced lymphocyte migration efficiently in vitro. We found by immunohistochemistry that Col IV and CCL21, CXCL13, and CXCL12 were colocalized in the basal lamina of HEVs. When injected s.c. into plt/plt mice, CCL21 colocalized at least partially with Col IV on the basal lamina of HEVs in draining lymph nodes. Collectively, our results suggest that Col IV contributes to the creation of a lymphoid chemokine-rich environment in the basal lamina of HEVs by binding an array of locally produced lymphoid chemokines that promote directional lymphocyte trafficking from HEVs into the lymphoid tissue parenchyma.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grants-in-Aid (17047025 and 17590432 to T.T.) and a grant for Advanced Research on Cancer (17014056 to M.M.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
2 Address all correspondence and reprint requests to Dr. Masayuki Miyasaka, Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Yamada-oka, Suita, Japan. E-mail address: mmiyasak{at}orgctl.med.osaka-u.ac.jp
3 Abbreviations used in this paper: LN, lymph node; PP, Peyer’s patch; HEV, high endothelial venule; GAG, glycosaminoglycan; DARC, Duffy Ag receptor for chemokines; AGM, angiomodulin; ECM, extracellular matrix; Col IV, collagen IV; CCL21-T, C-terminally truncated CCL21; LN-1, laminin-1; FN, fibronectin; RU, resonance unit; FRC, fibroblastic reticular cell.
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