Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

Thymus-derived, natural CD4+CD25+ regulatory T cells can educate peripheral CD4+CD25− cells to develop suppressive activity by poorly understood mechanisms. TGF-β has IL-2-dependent costimulatory effects on alloactivated naive, human CD4+ T cells and induces them ex vivo to become potent contact-dependent, cytokine-independent suppressor cells. In this study, we report that CD4+CD25+ cells are the targets of the costimulatory effects of IL-2 and TGF-β. These cells do not divide, but, instead, greatly increase the numbers of CD4+CD25− cells that become CD25+ cytokine-independent suppressor cells. These CD4+CD25+ regulatory cells, in turn, induce other alloactivated CD4+CD25− cells to become potent suppressor cells by mechanisms that, surprisingly, require both cell contact and TGF-β and IL-10. The suppressive effects of these secondary CD4+CD25+ cells depend upon TGF-β and IL-10. Moreover, both the naive CD4+ cells induced by IL-2 and TGF-β to become suppressor cells, and the subsequent CD4+CD25− cells educated by them to become suppressors express FoxP3. We suggest that the long-term effects of adoptively transferred natural-like CD4+CD25+ regulatory cells induced ex vivo are due to their ability to generate new cytokine-producing CD4+ regulatory T cells in vivo.

IL-2 and TGF-β both have important roles in the induction and maintenance of immunologic tolerance, but whether these cytokines act separately or together to achieve this effect is poorly understood. Although others have reported that IL-2 can directly enhance forkhead box protein P3 (Foxp3) transcription factor expression by natural CD4+CD25+ regulatory T cells, in this study, we report that the role of IL-2 on the generation of peripheral regulatory CD4+ cells is indirect. Ab neutralization studies and experiments with IL-2-deficient mice have revealed that IL-2 is required for TGF-β to induce naive CD4+CD25− cells to become CD25+ and express Foxp3, and develop the characteristic properties of CD4+CD25+ regulatory cells. This effect of IL-2 on the generation and expansion of these adaptive Foxp3+ regulatory cells is nonredundant, but IL-4, IL-7, and IL-15, other common γ-chain cytokines, could sustain Foxp3 expression. Because subjects with autoimmune diseases often have defects in the production of IL-2 and/or TGF-β, the generation of autologous T regulatory cells ex vivo with these cytokines for transfer in vivo may have considerable therapeutic potential.

An elusive goal in transplanting organs across histocompatibility barriers has been the induction of specific tolerance to avoid graft rejection. A considerable body of evidence exists that the thymus produces regulatory T cells that suppress the response of other T cells to antigenic stimulation. We report that TGF-β can induce certain CD4+ T cells in the naive (CD45RA+RO−) fraction in human peripheral blood to develop powerful, contact-dependent suppressive activity that is not antagonized by anti-TGF-β or anti-IL-10 mAbs. The costimulatory effects of TGF-β on naive CD4+ T cells up-regulated CD25 and CTLA-4 expression, increased their transition to the activated phenotype, but decreased activation-induced apoptosis. Suppressive activity was concentrated in the CD25+ fraction. These CD4+CD25+ regulatory cells prevented CD8+ T cells from proliferating in response to alloantigens and from becoming cytotoxic effector cells. Moreover, these regulatory cells exerted their suppressive activities in remarkably low numbers and maintained these effects even after they are expanded. Once activated, their suppressive properties were Ag nonspecific. Although <1% of naive CD4+ T cells expressed CD25, depletion of this subset before priming with TGF-β markedly decreased the generation of suppressive activity. This finding suggests that CD4+CD25+ regulatory T cells induced ex vivo are the progeny of thymus-derived regulatory T cells bearing a similar phenotype. The adoptive transfer of these regulatory T cells generated and expanded ex vivo has the potential to prevent rejection of allogeneic organ grafts.

Objective. Based on a small clinical series and previously published case reports, concordance for systemic lupus erythematosus (SLE) among monozygous (MZ) twins has been reported to be as high as 69%. Using a larger and less biased sample, we provide another estimate of this percentage.Methods. We established a registry of twins with SLE, based upon self-reports and information provided by the patients' physicians. We used DNA fingerprinting to validate the reported zygosity in a sample of these twins.Results. firmed by DNA fingerprinting in a subsample of 15 self-described MZ twins and 7 self-described DZ twins. All individuals had correctly predicted their zygosity.Conclusion. MZ concordance for SLE is similar to that for other autoimmune diseases and is much lower than previously believed.Concordance for disease in pairs of twins provides evidence of the relative etiologic contributions of genetic and environmental factors, as well as the timing of these effects. Low rates of concordance for disease over a lifetime, especially among monozygotic (MZ) twins, suggests a greater influence of environment; a large difference in concordance between MZ and dizygotic (DZ) twins suggests a greater influence of genetic determinants. However, for most diseases, there are no population-based twin concordancy data.Although the estimated annual incidence rate for systemic lupus erythematosus (SLE) is 5CL75 per million (1,2), no population-based studies of concordance rates in twins have been published. One case series reported that 69% of the MZ twin pairs were concordant (3), and anecdotal reports describe a similar proportion of concordance among MZ twin pairs. These reports also suggest that a much lower proportion of DZ twin pairs are concordant. In the study presented here, we used a larger sample size and an ascertainment mechanism that is less overtly biased in an effort to derive more meaningful data concerning the etiology of SLE.

Previously we reported that TGF-β has an important role in the generation and expansion of human “professional” CD4+CD25+ regulatory T cells in the periphery that have a cytokine-independent mechanism of action. In this study we used low-dose staphylococcal enterotoxin to induce T cell-dependent Ab production. We report that TGF-β induces activated CD4+CD25− T cells to become Th3 suppressor cells. While stimulating CD4+ cells with TGF-β modestly increased expression of CD25 and intracellular CTLA-4 in primary cultures, upon secondary stimulation without TGF-β the total number and those expressing these markers dramatically increased. This expansion was due to both increased proliferation and protection of these cells from activation-induced apoptosis. Moreover, adding as few as 1% of these TGF-β-primed CD4+ T cells to fresh CD4+ cells and B cells markedly suppressed IgG production. The inhibitory effect was mediated by TGF-β and was also partially contact dependent. Increased TGF-β production was associated with a decreased production of IFN-γ and IL-10. Depletion studies revealed that the precursors of these TGF-β-producing CD4+ suppressor cells were CD25 negative. These studies provide evidence that CD4+CD25+ regulatory cells in human blood consist of at least two subsets that have TGF-β-dependent and independent mechanisms of action. TGF-β has an essential role in the generation of both of these T suppressor cell subsets from peripheral T cells. The ability to induce CD4+ and CD8+ cells to become regulatory cells ex vivo has the potential to be useful in the treatment of autoimmune diseases and to prevent transplant rejection.

TGF-β has pleiotropic effects on T cell differentiation that are determined by other cytokines in the local environment. Whereas IL-2 and TGF-β induce naive T cells to become forkhead/winged helix transcription factor (Foxp3) positive regulatory cells (iTregs), the combination of IL-6 and TGF-β induces IL-17-producing cells (Th17). Moreover, IL-6 can use TGF-β produced by thymus-derived natural regulatory T cells (nTregs) to convert them to Th17 cells. In this study, we report a major difference between iTregs and nTregs. Treatment of iTregs with IL-6 did not affect Foxp3 expression, and their suppressive activity in vitro and in vivo was intact. To explain this difference between nTregs and iTregs, we found that IL-2 and TGF-β down-regulate IL-6 receptor expression and IL-6 signaling. The resistance of iTregs to Th17 conversion suggests that they can function more effectively than nTregs in an inflammatory milieu and emphasizes the central role of IL-2 in combination with TGF-β to maintain immunologic homeostasis.

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