Journal Article

CD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema

Ly, Catherine L., Rehal, Sonia, García Nores, Gabriela D., Savetsky, Ira L., Cuzzone, Daniel A., Kataru, Raghu P., Hespe, Geoffrey E., Yu, Jessie Z., Mehrara, Babak J., Gardenier, Jason C., Torrisi, Jeremy S., Huang, Jung Ju, Nitti, Matthew D.

2018

Overview

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. CD4 + T cells are critical for the development of lymphedema. Here the authors show how these cells contribute to lymphedema and identify that the sphingosine-1-phosphate receptor modulator FTY720 can prevent lymphedema in a mouse tail injury model by blocking the release of CD4 + T cells from the lymph nodes to the skin.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 13/51 / 14/35 / 38/77 / 64/60 / 692/698/1543/1565/1597/554/1898 / 692/699/4033 / Adoptive Transfer / Animals / Antigen-presenting cells / CD4 antigen / CD4 Antigens - genetics / CD4 Antigens - metabolism / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - immunology / Cell activation / Cell Differentiation - immunology / Chemokines / Dendritic cells / Dendritic Cells - immunology / Disease Models, Animal / Drainage / Female / Fibrosis / Fingolimod Hydrochloride - pharmacology / Fingolimod Hydrochloride - therapeutic use / Humanities and Social Sciences / Humans / Immunosuppressive Agents - pharmacology / Immunosuppressive Agents - therapeutic use / Leukocyte migration / Lymph nodes / Lymph Nodes - cytology / Lymph Nodes - pathology / Lymphangiogenesis - immunology / Lymphatic system / Lymphatic Vessels - cytology / Lymphatic Vessels - immunology / Lymphatic Vessels - pathology / Lymphedema / Lymphedema - drug therapy / Lymphedema - immunology / Lymphedema - pathology / Lymphocyte Activation - drug effects / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular chains / multidisciplinary / Pathogenesis / Phenotypes / Receptors, Lysosphingolipid - immunology / Receptors, Lysosphingolipid - metabolism / Science / Science (multidisciplinary) / Skin / Skin - cytology / Skin - immunology / Skin injuries / Sphingosine 1-phosphate / T cell receptors