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 and Babak J. Mehrara ()
Additional contact information
Gabriela D. García Nores: Memorial Sloan Kettering Cancer Center
Catherine L. Ly: Memorial Sloan Kettering Cancer Center
Daniel A. Cuzzone: Memorial Sloan Kettering Cancer Center
Raghu P. Kataru: Memorial Sloan Kettering Cancer Center
Geoffrey E. Hespe: Memorial Sloan Kettering Cancer Center
Jeremy S. Torrisi: Memorial Sloan Kettering Cancer Center
Jung Ju Huang: Memorial Sloan Kettering Cancer Center
Jason C. Gardenier: Memorial Sloan Kettering Cancer Center
Ira L. Savetsky: Memorial Sloan Kettering Cancer Center
Matthew D. Nitti: Memorial Sloan Kettering Cancer Center
Jessie Z. Yu: Memorial Sloan Kettering Cancer Center
Sonia Rehal: Memorial Sloan Kettering Cancer Center
Babak J. Mehrara: Memorial Sloan Kettering Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04418-y

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