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Author Notes:

Babak J. Mehrara, Email: mehrarab@mskcc.org

G.G.N., C.L.L., D.A.C., and B.J.M. conceived of the concept and designed the experiments. G.G.N., C.L.L., and D.A.C. developed methods. G.G.N., C.L.L. D.A.C., R.P.K., G.E.H., J.J.H., J.S.T., J.C.G., I.L.S., M.D.N., J.Z.Y., and S.R. performed the experiments. G.G.N., C.L.L. D.A.C., and B.J.M. analyzed the data. G.G.N., C.L.L. D.A.C., G.E.H., and B.J.M. prepared and edited the manuscript.

The authors are grateful to Mesruh Turkekul, Navid Paknejad, Sho Fujisawa, Yevgeniy Romin, Evan Darling, and Elvin Feng of the Molecular Cytology Core at Memorial Sloan Kettering Cancer Center for assistance with both histology and tissue imaging (NIH/NCI P30 CA008748). We would also like to thank Terry Helms, medical illustrator, at Memorial Sloan Kettering Cancer Center for her illustrations.

The authors declare no competing interests.

These authors contributed equally: Gabriela D. García Nores, Catherine L. Ly.

Subject:

Research Funding:

This work was supported by the following: NIH R01 HL111130-01 and R21-CA194882 grants awarded to B.J.M., Sharp Foundation Fund philanthropic gift awarded to B.J.M., NIH T32 CA009501-27 grant to G.D.G.N., NIH T32 CA9501-29 grant to C.L.L., NIH T32 CA009685-21A1 grant to D.A.C., Plastic Surgery Foundation pilot grant 350627 to G.D.G.N., and Plastic Surgery Foundation pilot grant 312436 to J.C.G.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • NITRIC-OXIDE
  • SECONDARY LYMPHEDEMA
  • MULTIPLE-SCLEROSIS
  • WOUND REPAIR
  • IN-VIVO
  • VEGF-C
  • LYMPHANGIOGENESIS
  • INFLAMMATION
  • MACROPHAGES
  • FIBROSIS

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

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Journal Title:

NATURE COMMUNICATIONS

Volume:

Volume 9, Number 1

Publisher:

, Pages 1970-1970

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author(s) 2018

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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