An immune paradox: How can the same chemokine axis regulate both immune tolerance and activation?

Abstract

Chemokines (chemotactic cytokines) drive and direct leukocyte traffic. New evidence suggests that the unusual CCR6/CCL20 chemokine receptor/ligand axis provides key homing signals for recently identified cells of the adaptive immune system, recruiting both pro-inflammatory and suppressive T cell subsets. Thus CCR6 and CCL20 have been recently implicated in various human pathologies, particularly in autoimmune disease. These studies have revealed that targeting CCR6/CCL20 can enhance or inhibit autoimmune disease depending on the cellular basis of pathogenesis and the cell subtype most affected through different CCR6/CCL20 manipulations. Here, we discuss the significance of this chemokine receptor/ligand axis in immune and inflammatory functions, consider the potential for targeting CCR6/CCL20 in human autoimmunity and propose that the shared evolutionary origins of pro-inflammatory and regulatory T cells may contribute to the reason why both immune activation and regulation might be controlled through the same chemokine pathway.

IL-17-producing γδ T cells switch migratory patterns between resting and activated states

“…While CCL20 is induced during inflammation, it is constitutively expressed in barrier tissues including skin, Peyer's patches and large intestine34353637. Both Ccr6 −/− and Ccr2 −/− Ccr6 −/− mice had markedly reduced number and frequency of γδ T cells expressing intermediate amounts of CD3/TCR in the dermis (γδT lo ), a population previously reported to produce IL-17 and distinct from TCR hi dendritic epidermal T cells22 (Fig.…”

CCR6+ Th cells in the cerebrospinal fluid of persons with multiple sclerosis are dominated by pathogenic non-classic Th1 cells and GM-CSF-only-secreting Th cells

“…Although CCR6 is known to be expressed by a number of pathogenic and regulatory CD4 + Th subsets (Comerford et al, 2010), the high expression of CCR6 on CSF CD4 + T cells in MS has been previously attributed to IL-17-secreting Th17 cells without determination of the actual frequency of these cells (Reboldi et al, 2009). Given that IL-17-secreting CD4 + T cells have been reported at relatively low frequencies in the blood and CSF, even in MS (Brucklacher-Waldert et al, 2009, Durelli et al, 2009), we therefore examined the expression of both IL-17A and IFNγ in relation to the expression of CCR6.…”

Distinct Chemokine Receptor Axes Regulate Th9 Cell Trafficking to Allergic and Autoimmune Inflammatory Sites

“…On the other hand, the apparently functionally opposing T H 17 and Treg subsets share expression of the chemokine receptor CCR6 (26). This receptor facilitates recruitment of these cells to sites of CCL20 production, a chemokine that is expressed constitutively and whose expression is strongly upregulated during acute inflammation at epithelial and mucosal sites (38). Subsets of T H 17 cells have also been variously reported to express CCR2, CCR4, CXCR4 and CXCR6 (39), while Treg function appears to additionally depend on CCR7 (40).…”

“…Subsets of T H 17 cells have also been variously reported to express CCR2, CCR4, CXCR4 and CXCR6 (39), while Treg function appears to additionally depend on CCR7 (40). It has been postulated that the balance between inflammatory T H 17 cells and Tregs infiltrating a given inflammatory site dictates whether prolonged and perhaps pathological inflammation or response resolution occurs (38). The results of the present study indicate that in contrast to these other T H subsets, T H 9 cells do not express chemokine receptors that are unique to the subset, but share chemokine receptors with other known subsets of T H cells.…”