CD4 + T Cells Are Activated in Regional Lymph Nodes and Migrate to Skin to Initiate Lymphedema

Nat Commun. 2018 May 17;9(1):1970. doi: 10.1038/s41467-018-04418-y.

Abstract

T cell-mediated responses have been implicated in the development of fibrosis, impaired lymphangiogenesis, and lymphatic dysfunction in secondary lymphedema. Here we show that CD4+ T cells are necessary for lymphedema pathogenesis by utilizing adoptive transfer techniques in CD4 knockout mice that have undergone tail skin and lymphatic excision or popliteal lymph node dissection. We also demonstrate that T cell activation following lymphatic injury occurs in regional skin-draining lymph nodes after interaction with antigen-presenting cells such as dendritic cells. CD4+ T cell activation is associated with differentiation into a mixed T helper type 1 and 2 phenotype, as well as upregulation of adhesion molecules and chemokines that promote migration to the skin. Most importantly, we find that blocking T cell release from lymph nodes using a sphingosine-1-phosphate receptor modulator prevents lymphedema, suggesting that this approach may have clinical utility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4 Antigens / genetics
  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Dendritic Cells / immunology
  • Disease Models, Animal
  • Female
  • Fingolimod Hydrochloride / pharmacology
  • Fingolimod Hydrochloride / therapeutic use
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Lymph Nodes / cytology
  • Lymph Nodes / pathology
  • Lymphangiogenesis / immunology
  • Lymphatic Vessels / cytology
  • Lymphatic Vessels / immunology
  • Lymphatic Vessels / pathology
  • Lymphedema / drug therapy
  • Lymphedema / immunology*
  • Lymphedema / pathology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Lysosphingolipid / immunology
  • Receptors, Lysosphingolipid / metabolism
  • Skin / cytology
  • Skin / immunology

Substances

  • CD4 Antigens
  • Immunosuppressive Agents
  • Receptors, Lysosphingolipid
  • Fingolimod Hydrochloride