Abstract

High endothelial venules (HEVs) effectively recruit circulating lymphocytes from the blood to lymph nodes. HEVs have endothelial cells (ECs) and perivascular sheaths consisting of fibroblastic reticular cells (FRCs). Yet, post-luminal lymphocyte migration steps are not well elucidated. Herein, we performed intravital imaging to investigate post-luminal T- and B-cell migration in popliteal lymph node, consisting of trans-EC migration, crawling in the perivascular channel (a narrow space between ECs and FRCs) and trans-FRC migration. The post-luminal migration of T cells occurred in a PNAd-dependent manner. Remarkably, we found hot spots for the trans-EC and trans-FRC migration of T- and B cells. Interestingly, T- and B cells preferentially shared trans-FRC migration hot spots but not trans-EC migration hot spots. Furthermore, the trans-FRC T-cell migration was confined to fewer sites than trans-EC T-cell migration, and trans-FRC migration of T- and B cells preferentially occurred at FRCs covered by CD11c+ dendritic cells in HEVs. These results suggest that HEV ECs and FRCs with perivascular DCs delicately regulate T- and B-cell entry into peripheral lymph nodes.

Highlights

  • Lymph nodes constantly recruit and return lymphocytes to and from the blood to facilitate rapid encounters between antigens and rare antigen-specific lymphocytes [1, 2]

  • Representative serial images (Figs 1C and S1) clearly show the multiples steps of T-cell migration across high endothelial venules (HEVs) composed of endothelial cells (ECs) and fibroblastic reticular cells (FRCs) through the perivascular channel: adhesion to ECs, intraluminal crawling, transEC migration, intra-PVC crawling, and trans-FRC migration, arriving at the lymph node parenchyma

  • To compare T-cell and B-cell migration, we performed the same experiment with B cells (Fig 1C). 3D tracking analysis showed that B cells required more time for trans-EC migration (3.0 ± 2.2 min) and trans-FRC migration (1.8 ± 0.9 min) than T cells

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Summary

Introduction

Lymph nodes constantly recruit and return lymphocytes to and from the blood to facilitate rapid encounters between antigens and rare antigen-specific lymphocytes [1, 2]. Circulating lymphocytes in the blood enter the lymph nodes via high endothelial venules (HEVs), the wall of which is composed mainly of two cellular components, endothelial cells (ECs) and fibroblastic reticular cells (FRCs) [2]. After the trans-EC migration, lymphocytes must crawl inside the perivascular channel (PVC) [1, 3], a narrow space between ECs and FRCs, and subsequently transmigrate across FRCs to arrive at the lymph node parenchyma. Efforts to elucidate post–trans-EC migration in HEVs have been made, a clear visualization and molecular mechanism of post–trans-EC migration, including the intra-PVC and trans-FRC migration of T- and B cells in HEVs, is still lacking

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