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

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.

Histopathologic Features of Lymphedema: A Molecular Review

“…Ogata et al found that the interaction between CD4+ T cells, specifically T helper type 1 and T helper type 17 cells, and macrophages promotes vascular endothelial growth factor C (VEGF-C) expression, which in turn led to the generation of immature and leaky lymphatic vessels that are essential for the development of initial edema [28]. Indeed, recent work from our own laboratory indicates CD4+ T cell activation is necessary and sufficient for the development of lymphedema [29,30]. Using the tail surgery and PLND models of lymphedema, Garcia Nores et al found that adoptive transfer of CD4+ T cells to CD4-deficient mice led to the development of lymphedema similar to that seen in WT mice; in contrast, no swelling was seen in CD4-deficient mice that did not undergo adoptive transfer [29].…”

“…Using the tail surgery and PLND models of lymphedema, Garcia Nores et al found that adoptive transfer of CD4+ T cells to CD4-deficient mice led to the development of lymphedema similar to that seen in WT mice; in contrast, no swelling was seen in CD4-deficient mice that did not undergo adoptive transfer [29]. These authors showed that following tail surgery or PLND, CD4+ T cells are released from draining lymph nodes and home to lymphedematous skin, a process dependent on dendritic cell (DC) activation [29]. Once in the skin, CD4+ T cells promote changes such as impaired lymphangiogenesis, fibrosis, and increased inducible Indeed, recent work from our own laboratory indicates CD4+ T cell activation is necessary and sufficient for the development of lymphedema [29,30].…”

“…These authors showed that following tail surgery or PLND, CD4+ T cells are released from draining lymph nodes and home to lymphedematous skin, a process dependent on dendritic cell (DC) activation [29]. Once in the skin, CD4+ T cells promote changes such as impaired lymphangiogenesis, fibrosis, and increased inducible Indeed, recent work from our own laboratory indicates CD4+ T cell activation is necessary and sufficient for the development of lymphedema [29,30]. Using the tail surgery and PLND models of lymphedema, Garcia Nores et al found that adoptive transfer of CD4+ T cells to CD4-deficient mice led to the development of lymphedema similar to that seen in WT mice; in contrast, no swelling was seen in CD4-deficient mice that did not undergo adoptive transfer [29].…”

“…Once in the skin, CD4+ T cells promote changes such as impaired lymphangiogenesis, fibrosis, and increased inducible Indeed, recent work from our own laboratory indicates CD4+ T cell activation is necessary and sufficient for the development of lymphedema [29,30]. Using the tail surgery and PLND models of lymphedema, Garcia Nores et al found that adoptive transfer of CD4+ T cells to CD4-deficient mice led to the development of lymphedema similar to that seen in WT mice; in contrast, no swelling was seen in CD4-deficient mice that did not undergo adoptive transfer [29]. These authors showed that following tail surgery or PLND, CD4+ T cells are released from draining lymph nodes and home to lymphedematous skin, a process dependent on dendritic cell (DC) activation [29].…”

“…These authors showed that following tail surgery or PLND, CD4+ T cells are released from draining lymph nodes and home to lymphedematous skin, a process dependent on dendritic cell (DC) activation [29]. Once in the skin, CD4+ T cells promote changes such as impaired lymphangiogenesis, fibrosis, and increased inducible nitric oxide synthase (iNOS) expression leading to lymphedema [29]. Increased expression of iNOS results in disruption of the endogenous nitric oxide gradient that regulates intrinsic lymphatic pumping [31,32].…”