Type 3 innate lymphoid cell-derived lymphotoxin prevents microbiota-dependent inflammation

Cell Mol Immunol. 2018 Jul;15(7):697-709. doi: 10.1038/cmi.2017.25. Epub 2017 Jun 5.


Splenomegaly is a well-known phenomenon typically associated with inflammation. However, the underlying cause of this phenotype has not been well characterized. Furthermore, the splenomegaly phenotype seen in lymphotoxin (LT) signaling-deficient mice is characterized by increased numbers of splenocytes and splenic neutrophils. Splenomegaly, as well as the related phenotype of increased lymphocyte counts in non-lymphoid tissues, is thought to result from the absence of secondary lymphoid tissues in LT-deficient mice. We now present evidence that mice deficient in LTα1β2 or LTβR develop splenomegaly and increased numbers of lymphocytes in non-lymphoid tissues in a microbiota-dependent manner. Antibiotic administration to LTα1β2- or LTβR-deficient mice reduces splenomegaly. Furthermore, re-derived germ-free Ltbr-/- mice do not exhibit splenomegaly or increased inflammation in non-lymphoid tissues compared to specific pathogen-free Ltbr-/- mice. By using various LTβ- and LTβR-conditional knockout mice, we demonstrate that retinoic acid-related orphan receptor γT-positive type 3 innate lymphoid cells provide the required active LT signaling to prevent the development of splenomegaly. Thus, this study demonstrates the importance of LT-mediated immune responses for the prevention of splenomegaly and systemic inflammation induced by microbiota.

Keywords: germ-free; lymphotoxin; microbiota; splenomegaly; type 3 innate lymphoid cells.

MeSH terms

  • Animals
  • Immunity, Innate*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Lymphocytes / immunology*
  • Lymphocytes / pathology
  • Lymphotoxin alpha1, beta2 Heterotrimer / genetics
  • Lymphotoxin alpha1, beta2 Heterotrimer / immunology*
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / immunology*
  • Mice
  • Mice, Knockout
  • Microbiota / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*


  • Ltbr protein, mouse
  • Lymphotoxin alpha1, beta2 Heterotrimer
  • Lymphotoxin beta Receptor
  • Receptors, Antigen, T-Cell, gamma-delta