Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure

Immunity. 2006 Sep;25(3):499-509. doi: 10.1016/j.immuni.2006.06.016. Epub 2006 Aug 24.


The development of spontaneous insulin-dependent diabetes mellitus is preceded by the organization of tertiary lymphoid organ (TLO) in situ, but its role in the development of tissue destruction and the cytokines that control such structures have not been fully defined. We have now observed that TNF superfamily 14 (TNFSF14) is upregulated in aged nonobese diabetic (NOD) pancreas with the appearance of TLO. Blockade of TNFSF14 signaling caused a substantial reduction in the expression of lymphotoxin beta receptor (LTbetaR)-controlled migration factors within the islets and disrupts organization of tertiary structures, leading to prevention of diabetes. Consistently, enhancing LTbetaR signaling by transgenic expression of TNFSF14 in the islets of NOD mice rapidly promoted de novo formation of local TLO, resulting in diabetes, even in the absence of draining lymph nodes (LN). Thus, the TNFSF14-LTbetaR pathway appears to be critical in the development and maintenance of TLO for the onset of diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Movement / immunology*
  • Cells, Cultured
  • Female
  • Humans
  • Immunoglobulins / genetics
  • Islets of Langerhans / cytology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism
  • Lymphocyte Activation / immunology*
  • Lymphoid Tissue / immunology*
  • Lymphoid Tissue / metabolism*
  • Lymphotoxin beta Receptor
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Prediabetic State / genetics
  • Prediabetic State / immunology
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / physiology*
  • Resting Phase, Cell Cycle / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology


  • Immunoglobulins
  • LTBR protein, human
  • Ltbr protein, mouse
  • Lymphotoxin beta Receptor
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor
  • TNFSF14 protein, human
  • Tnfsf14 protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha