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

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

doi:10.1038/s41467-018-04418-y

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.

Affiliations

¹ Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Suite MRI 1006, New York, NY, 10065, USA.
² Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Suite MRI 1006, New York, NY, 10065, USA. mehrarab@mskcc.org.

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