Taken jointly, current published evidence does not lend support to the notion that anti-TNF therapy can simply restore or promote Treg activity in RA patients. Directly contradictory to its well-known anti-inflammatory action, anti-TNF therapy also has at times been shown to promote inflammation. TNFR2-expressing CD4+FoxP3+ Tregs comprise ~40% of peripheral Tregs in normal mice and present the maximally suppressive subset of Tregs. In this review, studies describing the action of TNF on Chlormezanone (Trancopal) Treg function will be discussed. The role of Tregs in the autoimmune disorders and cancer as well as the effect of anti-TNF therapy on Tregs, especially in rheumatoid arthritis, will also be considered. Introduction CD4+FoxP3+ Regulatory T Cells Are Pivotal Regulators of Immune Responses The evidence that suppressive T cells downregulate DHCR24 antigen-specific response of effector T cells and maintain immune tolerance was reported as early as 1970s . In the mid-1990s, Sakaguchi et al.  identified CD4 cells which constitutively coexpressed CD25, the IL-2 receptor -chain, in normal rodents as potent suppressive regulatory T cells (Tregs), and showed that elimination of this population of cells elicited autoimmune responses. Subsequent studies extending over more than a decade have provided compelling evidence that CD4+FoxP3+ Tregs, comprising ~10% of peripheral CD4 cells, play an indispensable Chlormezanone (Trancopal) role in maintaining immune homeostasis and in suppressing deleterious excessive immune responses . Two major sources of Tregs, namely naturally occurring Tregs (nTregs) and induced Tregs (iTregs), are engaged in normal tolerogenic surveillance of self-antigens and prevent potential autoimmune responses. nTregs develop in the thymus and are exported to the periphery , and iTregs are converted from na?ve CD4 cells by TGF- in conjunction with T cell receptor (TCR) stimulation in the periphery . Tregs are preferentially self-reactive since their TCRs have higher affinity for self-antigens, and are similar to the TCR used by self-reactive pathogenic effector T cells (Teffs) . Foxp3, a member of the forkhead/winged-helix family of transcription factors, is usually a grasp regulator of Treg development and function , as shown by deficiency of Tregs and lethal autoimmunity caused by the mutation of FoxP3 in human patients with IPEX (immune dysregulation, Chlormezanone (Trancopal) polyendocrinopathy, enteropathy, X-linked) and its murine counterpart scurfy [reviewed in 7]. The characteristic phenotype of Tregs such as high expression of CD25, CTLA-4, GITR and low expression of CD127 was shown to be regulated by FoxP3 [reviewed in 8]. The activation, proliferation and effector functions of a large spectrum of immunocompetent cells, such as CD4 cells , CD8 cells , NK cells , NKT cells , dendritic cells , macrophages  and B cells  are susceptible to Treg-mediated suppression. The induction of Treg-suppressive activity is usually specific and requires antigenic stimulation through the TCR; however, the suppression exerted by Tregs is not antigen specific . Therefore, a wide range of immune responses can be inhibited by Tregs through bystander suppression . In addition to suppressing immune responses to auto-antigens, Tregs also attenuate host defense responses against pathogens [reviewed in 18] and tumor antigens [reviewed in 19]. The exact mechanism(s) of Treg-mediated suppression remain incompletely comprehended. The in vitro suppressive activity of Tregs depends on cell-to-cell contact as over a short distance . In addition, several molecules, such as IL-10, TGF-, CTLA-4, indoleamine 2,3-dioxygenase and granzyme/perforin are reported to contribute to the suppressive activity of Tregs [reviewed in 20]. IL-35 is usually reportedly expressed by mouse FoxP3+ Tregs and contributes to Treg function ; however, this immunosuppressive cytokine is not expressed by human Tregs [22, 23]. Tregs express CD39/ENTPD1 and CD73/ecto-5-nucleotidase, ectoenzymes which have the capacity to generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on Tregs and the adenosine A2A receptor on activated Teffs therefore may generate an immunosuppressive loop . Although Tregs are likely to use multiple mechanisms to suppress immune responses, CTLA-4 may have a dominant role. It has been recently shown that CTLA-4 was critically required for the function of Tregs.