Growth of Murine Splenic Tissue Is Suppressed by Lymphotoxin β-Receptor Signaling (LTβR) Originating from Splenic and Non-Splenic Tissues

PLoS One. 2016 Dec 9;11(12):e0166901. doi: 10.1371/journal.pone.0166901. eCollection 2016.


Development and maintenance of secondary lymphoid organs such as lymph nodes and spleen essentially depend on lymphotoxin β-receptor (LTβR) signaling. It is unclear, however, by which molecular mechanism their size is limited. Here, we investigate whether the LTβR pathway is also growth suppressing. By using splenic tissue transplantation it is possible to analyze a potential contribution of LTβR signaling inside and outside of the implanted tissue. We show that LTβR signaling within the endogenous spleen and within non-splenic tissues both significantly suppressed the regeneration of implanted splenic tissue. The suppressive activity positively correlated with the total number of LTβR expressing cells in the animal (regenerate weights of 115 ± 8 mg in LTβR deficient recipients and of 12 ± 9 mg in wild-type recipients), affected also developed splenic tissue, and was induced but not executed via LTβR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTβR dependent suppressive activity. Thus, LTβR dependent growth suppression is involved in regulating the size of secondary lymphoid organs, and might be therapeutically used to eradicate tertiary lymphoid tissues during autoimmune diseases.

MeSH terms

  • Animals
  • Blotting, Western
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Chemokine CCL19 / genetics
  • Chemokine CCL19 / metabolism
  • Chemokine CCL21 / genetics
  • Chemokine CCL21 / metabolism
  • Electrophoresis, Gel, Two-Dimensional
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / metabolism*
  • Mass Spectrometry
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Regeneration
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Spleen / growth & development
  • Spleen / metabolism*
  • Spleen / transplantation
  • Splenectomy
  • Stromal Cells / metabolism
  • Tissue Transplantation / methods*


  • Carrier Proteins
  • Chemokine CCL19
  • Chemokine CCL21
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Interleukin-17
  • Lymphotoxin beta Receptor
  • MFAP4 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3

Grant support

NMM: Ministry for Education, Science and Technological Development of Republic of Serbia; grant number: 175005; and Alexander von Humboldt-Foundation; grant number: DEU/1033146; JW: Deutsche Forschungsgemeinschaft; grant number: SFB 654, C4;