Manifold Roles of CCR7 and Its Ligands in the Induction and Maintenance of Bronchus-Associated Lymphoid Tissue

• Published in: Cell reports (Cambridge) Vol. 23; no. 3; pp. 783 - 795
• Main Authors: Fleige, Henrike, Bosnjak, Berislav, Permanyer, Marc, Ristenpart, Jasmin, Bubke, Anja, Willenzon, Stefanie, Sutter, Gerd, Luther, Sanjiv A., Förster, Reinhold
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.04.2018; Elsevier
• Subjects: BALT; CCL21; CCR7; DCs; HEVs; MVA; plt/plt; CCL21; DCs; BALT; MVA; CCR7; HEVs; plt/plt
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.072

The processes underlying the development and maintenance of tertiary lymphoid organs are incompletely understood. Using a Ccr7 knockout/knockin approach, we show that spontaneous bronchus-associated lymphoid tissue (BALT) formation can be caused by CCR7-mediated migration defects of dendritic cells (DCs) in the lung. Plt/plt mice that lack the CCR7 ligands CCL19 and CCL21-serine do not form BALT spontaneously because lung-expressed CCL21-leucine presumably suffices to maintain steady-state DC egress. However, plt/plt mice are highly susceptible to modified vaccinia virus infection, showing enhanced recruitment of immune cells as well as alterations in CCR7-ligand-mediated lymphocyte egress from the lungs, leading to dramatically enhanced BALT. Furthermore, we identify two independent BALT homing routes for blood-derived lymphocytes. One is HEV mediated and depends on CCR7 and L-selectin, while the second route is via the lung parenchyma and is independent of these molecules. Together, these data provide insights into CCR7/CCR7-ligand-orchestrated aspects in BALT formation. [Display omitted] •Blood-derived lymphocytes enter BALT via two independent routes•CCR7-associated DC migration defects lead to spontaneous BALT formation•Pulmonary CCL21-leucine alone maintains DC egress and prevents BALT formation•Aberrant lymphocyte migration promotes enhanced BALT formation in plt/plt mice Fleige et al. demonstrate that CCR7 and its ligands CCL19, CCL21-serine, and CCL21-leucine orchestrate multiple steps during induction and maintenance of bronchus-associated lymphoid tissue (BALT) including DC-based initial developmental processes as well as homing of blood-derived lymphocytes via HEVs to established BALT.