T-cell regulation in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by a chronic T-cell response that has escaped normal control mechanisms. This review summarizes recent insights in pathways that are functional in RA and that favor continuous and pathogenic T-cell activation.

T-cell activation is ultimately determined by positive signals from costimulatory molecules and negative signals from regulatory T cells. Blockade of the classic costimulatory pathway, CD28-CD80 or CD86, is beneficial in RA. Additional pathways that predominantly control the activation of memory and effector T cells are functionally important in synovial inflammation. Some of these costimulatory molecules (such as stimulatory killer cell immunoglobulin-like receptors and NKG2D) appear to be relatively specific for RA and not to play a role in normal immune responses. In addition to this predominance of positive signals, age-disproportionate decline in thymic activity in RA may lead to a diminution of regulatory T cells and loss of their negative signals.

The successful treatment trial of RA with CTLA-4Ig clearly documents the importance of T-cell costimulation in RA disease activity. Novel costimulatory pathways may be of even greater significance than CD28 in RA and may represent promising new therapeutic targets. The finding of reduced thymic activity in RA is exciting and will stimulate further studies of T-cell homeostasis and the function of regulatory cells.