Recently, agonist antibodies to glucocorticoid-induced tumor necrosis factor receptor (GITR) (tumor necrosis factor receptor superfamily 18) have been shown to neutralize the suppressive activity of CD4 ؉ CD25 ؉ regulatory T cells. It was anticipated that this would be the role of the physiological ligand. We have identified and expressed the gene for mouse GITR ligand and have confirmed that its interaction with GITR reverses suppression by CD4 ؉ CD25 ؉ T cells. It also, however, provides a costimulatory signal for the antigen-driven proliferation of naïve T cells and polarized T helper 1 and T helper 2 clones. RT-PCR and mAb staining revealed mouse GITR ligand expression in dendritic cells, macrophages, and B cells. Expression was controlled by the transcription factor NF-1 and potentially by alternative splicing of mRNA destabilization sequences.

Immune privilege was originally believed to be associated with particular organs, such as the testes, brain, the anterior chamber of the eye, and the placenta, which need to be protected from any excessive inflammatory activity. It is now becoming clear, however, that immune privilege can be acquired locally in many different tissues in response to inflammation, but particularly due to the action of regulatory T cells (Tregs) induced by the deliberate therapeutic manipulation of the immune system toward tolerance. In this review, we consider the interplay between Tregs, dendritic cells, and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T-cell and antigen-presenting cell activity, for example, by catabolism of the amino acids tryptophan and arginine and the induction of hemoxygenase and carbon monoxide. The induction of local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression.

Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.

Transplants tolerated through a process known as infectious tolerance evoke continuous recruitment of regulatory T (Treg) cells that are necessary to maintain the unresponsive state. This state is maintained long-term and requires continuous Ag exposure. It is not known, however, whether infectious tolerance operates through sustained recruitment of pre-existing regulatory cells, induction of regulatory cells, or both. Using mice deficient in natural Treg cells, we show here that quiescent donor dendritic cells (DC) laden with histocompatibility Ag can induce Treg cells de novo that mediate transplantation tolerance. In contrast, fully activated DC fail to do so. These findings suggest that DC incapable of delivering full activation signals to naive T cells may favor their polarization toward a regulatory phenotype. Furthermore, they suggest a role for quiescent endogenous DC in the maintenance of the tolerant state.

3349tions,laa additions of thiyl radicals to styrenes ( p --0.4 vs. and additions of C13G to styrenes ( p = -0.42 vs. a+)% and aliphatic olefins (p* = -0.2 to -0.4 vs. 8 or a*).% Table 111, the substituent effects for additions of PhCO2-, MeOO., and t-BuOO. to styrenes also resulted in small negative p values (p = -0.1 to -0.3 vs. a+) with poor correlations. That is, these oxy radicals add to styrenes as a weak electrophile. In contrast, acylperoxy radicals afford large negative p values ( p = -1 vs. a+), indicating the importance of polar effects in the radical additions to olefins.% The coincidence of p values between the reactions of Reo3., RC03H, and '02 is interesting. It is also interesting to recall that similar polar effects (Le., p = -0.3 As shown into -1.1 vs. a ' )are known in benzylic hydrogen abstract i o n~~' where benzyl radicals are being formed.In conclusion, a-diketones are photooxidized to 2 equiv of acylperoxy radical, which add to olefins 105-fold faster than alkylperoxy radicals and lead to effective epoxidations. Selective epoxidation of double bonds is possible since Reo3. is not reactive to sulfides, sulfoxides, and pyridine. The photoepoxidation proceeds at low temperature or in the presence of pyridine; then is application to acid-sensitive or unstable epoxides may be possible.2e The accompanying C-C cleavage of olefins proceeds via the addition of Reo2. or ROO.. Experimental SectionGLC analyses were performed with a Yanagimoto G180 gas (22) (a) Cadogan, J. I. G.; Sadler, I. H. (25) (a) The observed preference of the addition of Reo8. to C=C over H abstraction for c clohexene has been explained by ita highly U.