Introduction
Large numbers of memory T cells are found in the inflamed joint [
1‐
3], possibly facilitated by their enhanced capacity to adhere to vascular endothelium of inflamed synovium [
4,
5]. It is unclear, however, whether all memory T cells have the same propensity to migrate to the inflamed joint, independent of their antigen specificity. If this were the case then it would be expected that synovial fluid mononuclear cell (SFMC) proliferative responses to a wide range of antigens would be enhanced as compared with the peripheral blood mononuclear cell (PBMC) responses, provided that the individual had previously been exposed to those antigens. Alternatively, it has been suggested that patterns of antigen induced SFMC proliferation reflect an inciting or perpetuating antigenic stimulus [
6,
7]. In this situation, accumulation of a specific population of T cells in an inflamed joint would be reflected by an antigen-specific SFMC proliferative response. We hypothesized that all memory T cells would have the same propensity for migration into the joint, irrespective of their antigen specificities. The aim of the present study was to test the hypothesis in juvenile idiopathic arthritis (JIA) – a group of diseases characterized by chronic inflammation of synovial joints in childhood [
8].
Discussion
The majority of synovial fluid T cells from patients with JIA are of the memory phenotype [
2]. Memory T cells have an increased capacity to bind to inflamed endothelium because of increased expression of adhesion molecules and chemokine receptors [
9].
Previous studies of patients with JIA and reactive arthritis demonstrated that antigen-induced T cell proliferative responses were usually more vigorous in the synovial fluid than in peripheral blood, suggesting nonspecific recruitment of memory T cells into the inflamed joint [
7,
10‐
12]. In contrast, we found two distinct patterns of T cell antigen responsiveness: diverse and restricted proliferation. Proliferation to all of the antigens was more vigorous in the SFMCs than in the PBMCs in the group of patients who exhibited a diverse response. This pattern of response would be expected if the synovial fluid memory T cells were recruited to the inflamed joint as a consequence of their memory phenotype rather than specific antigens. The group of patients with a restricted response, however, demonstrated less vigorous proliferative responses to TT and/or SLO in the synovial fluid compartment than in the peripheral blood. This pattern of response suggests that, in some patients, memory T cells specific for TT or SLO preferentially remain within the peripheral blood compartment (i.e. synovial fluid T cells may not be recruited to the inflamed joint as a consequence of their memory phenotype alone).
We observed a striking association between the pattern of proliferation and the acute phase response; those patients with a high acute phase response exhibited a diverse pattern, whereas those with little or no acute phase response tended to show a restricted pattern of responses to the antigen panel. This was supported by studies of serial synovial fluid and peripheral blood samples from three patients, in whom a high acute phase response was associated with a diverse pattern that reverted to a restricted pattern when the acute phase proteins normalized.
Possible explanations for this association may lie in the direct actions of the acute phase proteins themselves, or indirectly via factors that govern the acute phase response. CRP has chemotactic properties for leucocytes [
13] and T cells may bind directly to CRP, resulting in inhibition of T cell function [
14,
15]. Although CRP does not accumulate at high concentrations within inflamed tissues [
16], it is possible that circulating CRP or other acute phase proteins exert a direct action on T cells in the peripheral blood. Acute phase proteins may influence the expression of adhesion molecules on joint endothelium, and T cells and chemokine expression within the joint. Serum amyloid A may accumulate in inflamed tissues where it can act as a chemoattractant for neutrophils, monocytes and lymphocytes, and it is possible that the accumulation of activated CD14
+ monocytes may contribute to the different proliferative patterns seen [
17‐
19]. Also, JIA patients with systemic disease have increased chemokine expression in the synovial fluid [
20]. Tumour necrosis factor-α, which correlates with acute phase protein levels in patients with JIA [
21], has been shown to upregulate adhesion molecules on endothelial cells [
22] as well as enhancing chemokine induced recruitment of memory T cells into inflammatory sites [
23].
It is interesting that the antigens that induced vigorous SFMC proliferation in patients exhibiting a 'restricted pattern' were those associated with Gram-negative enteric bacteria. T cells from the gut have enhanced capacity to bind to synovial endothelial cells, possibly because of shared characteristics of adhesion molecules at the two sites [
24‐
26]. It is conceivable that, in 'restricted pattern' patients, T cells that have been through the gut or its mucosal associated lymphoid tissue, and exposed to enteric antigens, are preferentially able to bind to the synovial endothelium and are therefore selectively recruited to the synovial compartment. In 'diverse pattern' patients, however, high levels of proinflammatory cytokines, such as tumour necrosis factor-α, may upregulate chemokine-induced recruitement of all memory T cells to the synovial compartment. In this situation, vigorous immune responses may be observed to all tested antigens, and the relative specificity of proliferative responses to enteric bacteria by gut-associated T cells may be obscured.
An increased percentage of JIA synovial fluid T cells expressed the mucosal integrin αEβ7 and the γδ TCRs, implying that mucosal T cells have a propensity to migrate to the inflamed joint. Mucosal memory T cells express α4β7, which facilitates homing to the gut [
27]. Once within the mucosal site, α4β7 is downregulated and αEβ7 is upregulated, which may assist in T cell retention within the mucosal site [
28,
29]. The results of our studies support a similar process of 'integrin switching' in the joint.
Our findings are in agreement with the observation that CXCR3, a cell surface receptor for the proinflammatory chemokines inducible protein (IP)-10 and monokine induced by interferon-γ (Mig), is expressed on JIA synovial fluid T cells [
30,
31]. It is possible that CXCR3 expression favours synovial T cell accumulation in the absence of an acute phase response.
Conclusion
We propose the following model. Proinflammatory cytokines that induce a high acute phase response also favour the recruitment of a diverse memory T cell repertoire to the joint, independent of the antigen specificity of the memory T cells. However, when there is little systemic inflammation (low acute phase response), only those T cells with an intrinsic ability to bind to synovial endothelium, such as mucosal T cells, migrate into the synovial compartment.