Initial T cell activation is dependent on T cell receptor triggering and costimulatory signaling through CD28-CD80/CD86 [10,11]. APCs such as dendritic cells (DCs), macrophages, B cells and follicular DCs can provide both of these signals. APCs that cannot provide costimulatory signals are unable to activate naïve T cells unless a second signal is provided by accessory APCs. The costimulatory molecules CD80/CD86 are expressed at varying levels by APCs in the synovium. Expression of CD80 is generally low, while the expression of CD86 is relatively high and is expressed on several APCs including DCs, B cells and macrophages [12,13]. It has been suggested that CD80/CD86 interactions influence the development of T helper (Th)1 and Th2 cells, where Th2 polarization is dependent on signals through the CD80 molecule [14*,15]. T cells in the synovium are of Th1 type, and even though the secretion of IFNγ is low, the Th1 cytokine IL-17 can be found in high levels [16,17]. Expression of CD86 and lack of CD80 then correlates with the dominant population of Th1 cells in the synovium [16,18]. APCs in the synovium might therefore be capable of the initial activation of T cells through the Th1 pathway by the expression of CD86 and secretion of IL-12. It has been shown in various models that blocking the CD28 signaling pathway can prevent or treat autoimmune diseases [19,20]. Studies in MLR/lpr mice lacking CD28 suggest that CD28 is most probably a regulator in the induction of autoimmune diseases. Arthritis is abolished and autoantibody production is suppressed in these mice, but the accumulation of abnormal T cells is almost unchanged .
The memory population of Th1 cells in the synovium has an increased number of CD28-negative cells . Memory T cells, however, have a lower requirement for CD28 signaling compared with naïve T cells and can respond to T cell receptor signaling alone . A much greater range of APCs can therefore stimulate memory T cells than that which stimulates naïve T cells. In addition, effector T cells are even less dependent on costimulatory signals and can respond to many types of APC including resting B cells and macrophages . APCs in the synovium generally express low levels of CD80/86, but still might function as APCs for memory/effector T cells and maintain the inflammatory response by continuously activating synovial memory T cells.
In addition to CD28/CD86-80 costimulation, CD40-CD40L has been shown to contribute to T cell activation, both by independently costimulating T cells and, at least in part, by upregulating CD80/CD86 molecules on APCs [14*,25]. The CD40 pathway is particularly thought to be important for amplification of the T cell response, as blocking the CD40 signaling pathway has been shown to inhibit Th1 differentiation and maintenance of the immune response . DCs, B cells and macrophages express CD40 in the synovium, and these APCs may be of particular importance for the disease pathogenesis.