Dendritic cell trafficking: More than just chemokines

Abstract

Dendritic cells (DC) are professional antigen presenting cells. To accomplish their biological function they need to undergo a complex pattern of migration which includes their localization to both peripheral non-lymphoid tissues and secondary lymphoid organs. In the absence of correct tissue localization, DC fail to promote proper immune responses. The first description of chemotactic factors active on DC was published by this group 10 years ago. Since then, it was described that multiple signals are able to regulate the migration of DC in vitro and in vivo. These signals include nonchemokine chemotactic agonists, lipid mediators and membrane proteins. This review summarizes this large body of information and focuses on the complexity of the process of DC trafficking.

Introduction

Dendritic cells (DC) are potent antigen presenting cells with a unique ability in inducing T and B cell responses as well as immune tolerance [1], [2], [3], [4]. DC reside in an immature state in peripheral tissues where they exert a sentinel function for incoming antigens [1], [2], [3], [4]. Upon microbial contact or stimulation by inflammatory cytokines, DC uptake antigens and traffic via the afferent lymphatics into the T cell area of the draining lymph node to initiate immune responses [2], [5], [6], [7]. There is evidence that steady-state migration of DC into the lymph node also occurs in normal conditions and may serve to tolerize T cells against self and non-dangerous antigens [1]. Migration of DC into tissues depends on a cascade of discrete events, including chemokine production and regulation of chemokine receptors [5], [6], [8], [9].

DC are a heterogeneous population that posses unique homing properties [2], [10]. Myeloid blood CD11c⁺ DC can migrate in response to a wide array of inflammatory chemotactic agonists produced at the peripheral sites of infection and immune reaction [7], [11], [12]. On the other hand, CD123⁺ plasmacytoid DC are believed to enter lymph nodes across blood high endothelial venules [13]. The expression and regulation of functional chemotactic receptors is likely to be responsible for the different distribution of DC subsets in vivo.

The proper localization of DC to secondary lymphoid organs and their recruitment at sites of inflammation in response to chemotactic stimuli are critical events for optimal immune response [14], [15], [16]. Recent work has documented that a number of chemotactic agonists, different from chemokines, play a relevant role in DC subset recruitment [12], [17], [18], [19], [20]. Furthermore, multiple experimental evidences have shown that chemokine receptor expression is not predictive of DC migration since multiple factors, including prostaglandins, leukotrienes, sphingosine1-phosphate, extracellular nucleotides and some membrane proteins (e.g. CD38) play an important role in the regulation of chemokine receptor function [10], [21], [22], [23], [24]. Therefore, DC migration in vivo is a tightly regulated process controlled at the level, of chemokine production and chemokine receptor expression and function.