Global lymphoid tissue remodeling during a viral infection is orchestrated by a B cell-lymphotoxin-dependent pathway.
Adaptive immune responses are characterized by substantial restructuring of secondary lymphoid organs. The molecular and cellular factors responsible for virus-induced lymphoid remodeling are not well known to date. Here we applied optical projection tomography, a mesoscopic imaging technique, for a global analysis of the entire 3-dimensional structure of mouse peripheral lymph nodes (PLNs), focusing on B-cell areas and high endothelial venule (HEV) networks. Structural homeostasis of PLNs was characterized by a strict correlation between total PLN volume, B-cell volume, B-cell follicle number, and HEV length. After infection with lymphocytic choriomeningitis virus, we observed a substantial, lymphotoxin (LT) beta-receptor-dependent reorganization of the PLN microarchitecture, in which an initial B-cell influx was followed by 3-fold increases in PLN volume and HEV network length on day 8 after infection. Adoptive transfer experiments revealed that virus-induced PLN and HEV network remodeling required LTalpha(1)beta(2)-expressing B cells, whereas the inhibition of vascular endothelial growth factor-A signaling pathways had no significant effect on PLN expansion. In summary, lymphocytic choriomeningitis virus-induced PLN growth depends on a vascular endothelial growth factor-A-independent, LT- and B cell-dependent morphogenic pathway, as revealed by an in-depth mesoscopic analysis of the global PLN structure.
Kumar
Varsha
V
Theodor Kocher Institute, University of Bern, Bern, Switzerland.
Scandella
Elke
E
Danuser
Renzo
R
Onder
Lucas
L
Nitschké
Maximilian
M
Fukui
Yoshinori
Y
Halin
Cornelia
C
Ludewig
Burkhard
B
Stein
Jens V
JV
D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D053259:Lymphotoxin beta Receptor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C505699:Ltbr protein, mouse; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse