Scavenging of soluble and immobilized CCL21 by ACKR4 regulates peripheral dendritic cell emigration

Significance The immune system relies on coordinated interactions between motile cells guided by molecules known as chemokines. However, processes that control chemokine distribution in complex in vivo microenvironments are poorly understood. Dendritic cells in barrier tissues require the chemokine CCL21 to enter lymphatic vessels during tissue egress. Here, we demonstrate that ACKR4 shapes CCL21 distribution in barrier tissues and prevents leakage of CCL21 from the tissue. Without ACKR4, extracellular CCL21 gradients in barrier sites are saturated and nonfunctional, DCs cannot home directly to lymphatic vessels, and excess soluble CCL21 from peripheral tissues pollutes lymph nodes. The results increase understanding of regulation of dendritic cell egress and chemokine distribution in vivo and raise new questions regarding the function of solubilized CCL21.