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Treatment with ex vivo-generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG)[sub.35-55]/IA[sup.b] (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer-reactive, Foxp3[sup.+] T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3[sup.+] T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4[sup.+]Foxp3[sup.+] T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation., Author(s): Thomas Korn [1]; Jayagopala Reddy [1]; Wenda Gao [2]; Estelle Bettelli [1]; Amit Awasthi [1]; Troels R Petersen [3]; B Thomas Backstrom [3]; Raymond A Sobel [4]; Kai W [...]

Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private [alpha]-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor [beta]- and [gamma]-chains. The [gamma]-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the [gamma]-chain is called the common [gamma] or [gamma]-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the [gamma]-c expression. Decreased [gamma]-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo., Author(s): Xian Chang Li (corresponding author) [1]; Gulcin Demirci [1]; Sylvie Ferrari-Lacraz [1]; Chris Groves [2]; Anthony Coyle [2]; Thomas R. Malek [3]; Terry B. Strom [1] In contrast to [...]

Immune tolerance cannot be induced in mice with defective T-cell apoptosis. This shows that deletion of alloreactive T cells is necessary for inducing tolerance to a transplant.

Co-stimulation blockade of the CD28-B7 and CD40-CD40 ligand interactions prevents the proliferation of alloreactive T cells. Adding rapamycin causes apoptosis of alloreactive T cells and allograft tolerance.

Author(s): Xian Chang Li [1]; Terry B. Strom [1] THE SUCCESS of allogeneic hematopoietic stem cell engraftment across major histocompatibility complex barriers can be promoted by passenger cells that are [...]

Author(s): Yongsheng Li [1]; Terry B. Strom [1] Li and Strom reply Dharnidharka and colleagues raise an important point. Co-stimulation blockade using anti-CD154 and CTLA4-Ig, albeit remarkably effective in many [...]

Here we present methods to longitudinally track islet allograft–infiltrating T cells in live mice by endoscopic confocal microscopy and to analyze circulating T cells by in vivo flow cytometry. We developed a new reporter mouse whose T cell subsets express distinct, 'color-coded' proteins enabling in vivo detection and identification of effector T cells (Teff cells) and discrimination between natural and induced regulatory T cells (nTreg and iTreg cells). Using these tools, we observed marked differences in the T cell response in recipients receiving tolerance-inducing therapy (CD154-specific monoclonal antibody plus rapamycin) compared to untreated controls. These results establish real-time cell tracking as a powerful means to probe the dynamic cellular interplay mediating immunologic rejection or transplant tolerance. [ABSTRACT FROM AUTHOR]