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Review
. 2019 Mar 18:10:470.
doi: 10.3389/fimmu.2019.00470. eCollection 2019.

Regulation of Immune Function by the Lymphatic System in Lymphedema

Raghu P Kataru  1 , Jung Eun Baik  1 , Hyeung Ju Park  1 , Itay Wiser  1 , Sonia Rehal  1 , Jin Yeon Shin  1 , Babak J Mehrara  1
Affiliations
Review

Regulation of Immune Function by the Lymphatic System in Lymphedema

Raghu P Kataru et al. Front Immunol. .

Abstract

The lymphatic vasculature has traditionally been thought to play a passive role in the regulation of immune responses by transporting antigen presenting cells and soluble antigens to regional lymph nodes. However, more recent studies have shown that lymphatic endothelial cells regulate immune responses more directly by modulating entry of immune cells into lymphatic capillaries, presenting antigens on major histocompatibility complex proteins, and modulating antigen presenting cells. Secondary lymphedema is a disease that develops when the lymphatic system is injured during surgical treatment of cancers or is damaged by infections. We have used mouse models of lymphedema in order to understand the effects of chronic lymphatic injury on immune responses and have shown that lymphedema results in a mixed T helper cell and T regulatory cell (Treg) inflammatory response. Prolonged T helper 2 biased immune responses in lymphedema regulate the pathology of this disease by promoting tissue fibrosis, inhibiting formation of collateral lymphatics, decreasing lymphatic vessel pumping capacity, and increasing lymphatic leakiness. Treg infiltration following lymphatic injury results from proliferation of natural Tregs and suppresses innate and adaptive immune responses. These studies have broad clinical relevance since understanding how lymphatic injury in lymphedema can modulate immune responses may provide a template with which we can study more subtle forms of lymphatic injury that may occur in physiologic conditions such as aging, obesity, metabolic tumors, and in the tumor microenvironment.

Keywords: Th2 type T cells; fibrosis; immune function; inflammation; lymphatic vessels.

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Figures

Figure 1
Figure 1
The proposed pathophysiology of secondary lymphedema. Lymphatic injury results in activation of DCs and maturation of DCs. Activated DCs migrate to skin draining lymph node(s) through the interaction of their chemokine receptors (CCR7) and chemokine (CCL19, CCL21) produced by LECs. Within the lymph node, activated DCs interact via T cell receptors and co-stimulatory molecules (CD28) with naïve CD4+ T cells resulting in T cell activation and Th1/Th2 differentiation. Activated CD4+ T cells express skin homing receptors (CCR4, CCR10, and CLA), are actively released from the lymph node into the systemic circulation, and home preferentially migrate to the skin in the area of lymphatic injury following gradients of CCL17, CCL27 which are mainly produced by keratinocyte. Upon the arrival in the skin, activated CD4+ T cells produce the Th1 (IFN-γ) or Th2 inflammatory mediators (IL-4, IL-13, TGF-β1), which promote lymphedema development by causing fibroadipose tissue deposition, impair lymphangiogenesis, decreased lymphatic pumping, increased lymphatic leakiness, and chronic inflammation.
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