ARTHRITIS & RHEUMATISM Vol. 56, No. 3, March 2007, pp 710–713 DOI 10.1002/art.22415 © 2007, American College of Rheumatology EDITORIAL Regulatory T Cell Defects in Rheumatoid Arthritis Sujata Sarkar and David A. Fox Regulatory T (Treg) cells have emerged as a distinct subset of lymphocytes that are responsible for limiting immune responses and avoiding pathologic au- toimmunity. Evidence is accumulating that defects in Treg function are important in immune-mediated dis- eases such as rheumatoid arthritis (RA). We discuss herein the biology of Treg cells and emphasize what is known about Treg dysfunction in RA. Treg cells, a component of immune homeostasis Specific immunologic tolerance to self antigens requires the immune system to discriminate between self and nonself. Elimination of self-reactive T cells in the thymus during T cell development leads to central tolerance. Peripheral tolerance is designed both to con- trol responses to foreign antigens encountered in the periphery and to maintain tolerance to self antigens. While tolerance is mediated by a variety of mecha- nisms, work over the last 12 years has established a critical role for a specific subset of T cells known as regulatory T cells. How are Treg cells identified? Interest in regulatory T cells represents a rein- carnation of immunologic concepts that were first pro- posed decades ago. The initial reports of what were then called T suppressor cells appeared in the 1970s, but these cells were difficult to characterize, and they fell out of favor by the late 1980s, despite intriguing evidence of defective T suppressor cell dysfunction in systemic rheumatic diseases. Subsequent experiments performed by Sakaguchi et al (1) reinvigorated interest in what were renamed regulatory T cells, and focused greater attention on the regulation of T cell function by a subset of CD4+ cells, in contrast to an earlier focus on the suppression of antibody production by CD8+ suppressor cells. Sakaguchi showed that adoptive trans- fer of CD4+,CD25– T cells into athymic nude mice resulted in autoimmune disease in the recipient ani- mals, which was ameliorated by transfer of CD4+, CD25+ T cells. CD25, the interleukin-2 receptor -chain (IL-2R), is also expressed by activated T cells, but the CD4+,CD25 high cells among the CD4+,CD25+ subset are considered to be Treg cells. In general, the characteristics of mouse and human CD4+,CD25+ Treg cells are similar. Typically, 8–12% of CD4+ T cells are CD25+ Treg cells. How do Treg cells develop? Current data suggest that there are 2 subsets of Treg cells, the CD4+,CD25+ natural Treg (nTreg) cells, which mediate central tolerance, and induced Treg (iTreg) cells, which mediate peripheral tolerance. Natu- ral Treg cells develop in the thymus, have a repertoire similar to that of conventional T cells but more skewed toward recognition of autoantigens, undergo clonal ex- pansion upon antigen exposure, and yet maintain their suppressive phenotype. The thymic cellular events un- derlying the development and maturation of nTreg cells are not fully understood. It is possible that some thymo- cytes receive a strong signal via their T cell receptor (TCR) and CD28, escape negative selection, and differ- entiate into nTreg cells. The nTreg cells then migrate to the periphery and suppress autoreactive T cells, thus suppressing autoimmunity. Stimulation through the CD28 molecule is also required for the survival and proliferation of nTreg cells in the periphery. These cells express CD25, forkhead box P3 (FoxP3)/winged-helix transcription factor, cytotoxic T lymphocyte–associated Supported by the NIH (grant R01-AR-38477). Dr. Sarkar is recipient of a Fellowship Award from the Arthritis Foundation. The University of Michigan receives NIH funding as a Rheumatic Disease Core Center. Sujata Sarkar, MD, David A. Fox, MD: University of Michi- gan, Ann Arbor. Address correspondence and reprint requests to David A. Fox, MD, Division of Rheumatology, Room 3918 Taubman Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: dfox@umich.edu. Submitted for publication October 25, 2006; accepted in revised form November 20, 2006. 710