Expression of the inflammatory chemokines CCL5, CCL3 and CXCL10 in juvenile idiopathic arthritis, and demonstration of CCL5 production by an atypical subset of CD8+ T cells

The hyperplastic and highly vascular synovial tissue that characterises the synovitis of juvenile idiopathic arthritis (JIA) has a dense infiltrate of activated inflammatory T cells, as well as B cells, macrophages and dendritic cells [1-3]. To enter the inflamed site, these cells migrate across an endothelial barrier, a complex process that involves molecular interactions between several receptor-ligand pairs [4,5]. Chemokines are small secreted chemo-attractant molecules involved in such leukocyte trafficking, as well as playing important roles in lymphoid homeostasis and development [6-8]. Functionally distinct subsets of leukocytes express different chemokine receptors: thus, recently activated, effector and memory T cells express high levels of the receptors that bind inflammatory chemokines, thought to facilitate their accumulation at inflammatory sites, compared to na？ve cells. Similarly, chemokine receptor expression can be used to distinguish Th-1 T cells (which typically express CXCR3 and CCR5) from Th-2 populations (typically CCR3 positive) [9-11], or 'central' from 'effector' memory T cell populations [12].As well as mediating chemoattraction, chemokines may also play a direct role in the activation of leukocytes. For example, the chemokine CCL5 (also known as 'regulated upon activation, normally T cell expressed and secreted' (RANTES)) activates T cells when in high concentration through a tyrosine kinase pathway [13,14], leads to production of IFNγ by T cells [15] and may induce maturation of dendritic cells [16]. Thus, migration of T cells under a chemokine gradient into an inflamed site such as the joint in JIA may itself lead to further T cell activation. Furthermore, several of the inflammatory chemokines have recently been shown to be able to increase T cell activation during T cell-antigen presenting cell interaction through their recruitment to the immunological synapse [17].We have previously shown that inflammatory T cells in the joint in JIA