Regulatory T cells in rheumatoid arthritis

The development of autoimmune diseases requires the breakdown of immunologic self-tolerance that usually controls self and non-self discrimination [1]. The primary mechanism that leads to tolerance to self-antigens is the thymic deletion of self-reactive T cells ('negative selection'). However, because some self-reactive T cells escape this process physiologically and autoreactive CD4+ T cells are present in the peripheral circulation of healthy individuals, where they retain their capacity to initiate autoimmune inflammation [2], negative selection in the thymus is not sufficient to prevent the activation of self-reactive T cells in the periphery [3]. Thus, regulatory mechanisms in the peripheral immune system are required to protect against both the generation of self-directed immune responses and the consequence of this, namely the initiation of autoimmune diseases. It is likely that one such mechanism of peripheral tolerance involves the active suppression of T cell responses by CD4+ T cells with regulatory capacity, of which a major subset are the CD4+CD25+ regulatory T cells.Regulatory T cells were first discovered in experimental animal models and were subsequently identified in humans. In 1971, a unique subpopulation of T cells was described that was capable of downregulating or suppressing the functions of other cells [4]. These regulatory ('suppressor') T cells had the capacity to transfer antigen-specific tolerance to naive animals. However, the concept of active suppression by T cells lost acceptance because of several technical problems. For example, it was not possible to identify specific cell-surface markers associated with suppressor T cells. Further, when T cell receptor genes were analyzed, suppressor T cells did not seem to have functional gene rearrangements [5]. Most remarkably, soluble suppressor factors, which were believed to be the molecular mechanism of action of suppressor T cells, were thought to be encoded by the murine I–J locus of the