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Biomedical subjects

Shimon Sakaguchi

Publications and source records attributed to Shimon Sakaguchi.

At least 73 records · Page 4Linked to original sources
PubMed2004

CD4+ Tregs and immune control.

Recent years have seen Tregs become a popular subject of immunological research. Abundant experimental data have now confirmed that naturally occurring CD25+CD4+ Tregs in particular play a key role in the maintenance of self tolerance, with their dysfunction leading to severe or even fatal immunopathology. The sphere of influence of Tregs is now known to extend well beyond just the maintenance of immunological tolerance and to impinge on a host of clinically important areas from cancer to infectious diseases. The identification of specific molecular markers in both human and murine immune systems has enabled the unprecedented investigation of these cells and should prove key to ultimately unlocking their clinical potential.

Animals↗
PubMed2003

4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells.

4-1BB (CD137) is a costimulatory molecule involved in the activation and survival of CD4, CD8, and natural killer cells. Although a great deal has been learned as to how 4-1BB-mediated signaling governs the immunity of conventional T cells, the functional role of 4-1BB in the context of CD4(+)CD25(+) regulatory T cell (Tr) activation is largely unknown. Using 4-1BB-intact and -deficient mice, we investigated the effect of the 4-1BB/4-1BB ligand pathway on the suppressive function of Tr cells. Our data indicate that although 4-1BB is expressed on Tr cells, its contribution to their proliferation is minimal. We also showed that signaling through the 4-1BB receptor inhibited the suppressive function of Tr cells in vitro and in vivo. It is interesting that anti-4-1BB-mediated but not anti-GITR-directed inhibition was more potent when Tr cells were preactivated. Collectively, these data indicate that 4-1BB signaling is critical in Tr cell immunity.

4-1BB Ligand↗
PubMed2003

A paragon of self-tolerance: CD25+CD4+ regulatory T cells and the control of immune responses.

The interest in naturally arising regulatory T (TR) cells as a paradigm for maintaining immunological self-tolerance has undergone an explosive re-emergence in recent years. This renaissance was triggered by several key experimental observations and the identification of specific molecular markers that have enabled the isolation and experimental manipulation of these cells. Although their existence was once controversial, a large body of evidence now highlights the critical roles of TR cells in maintaining immunological self-tolerance. Furthermore, abnormality of natural TR cells can be a primary cause of autoimmune and other inflammatory diseases in humans.

Journal Article↗
PubMed2003

Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.

Rheumatoid arthritis (RA), which afflicts about 1% of the world population, is a chronic systemic inflammatory disease of unknown aetiology that primarily affects the synovial membranes of multiple joints. Although CD4(+) T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4(+) T cells are generated and activated. Given that highly self-reactive T-cell clones are deleted during normal T-cell development in the thymus, abnormality in T-cell selection has been suspected as one cause of autoimmune disease. Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells, causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA.

Amino Acid Sequence↗
PubMed2003

Control of regulatory T cell development by the transcription factor Foxp3.

Regulatory T cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Little is known, however, about the molecular mechanism of their development. Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells. Furthermore, retroviral gene transfer of Foxp3 converts naïve T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+ regulatory T cells. Thus, Foxp3 is a key regulatory gene for the development of regulatory T cells.

Animals↗
PubMed2003

Control of autoimmunity by naturally arising regulatory CD4+ T cells.

Naturally acquired immunological self-tolerance is not entirely accounted for by clonal deletion, anergy, and ignorance. It is now well established that the T cell-repertoire of healthy individuals harbors self-reactive lymphocytes with a potential to cause autoimmune disease and these lymphocytes are under dominant control by a unique subpopulation of CD4+ T cells now called regulatory T cells. Efforts to delineate these Treg cells naturally present in normal individuals have revealed that they are enriched in the CD25+ CD4+ population. The identification of the CD25 molecule as a useful marker for naturally arising CD4+ regulatory T cells has made it possible to investigate many key aspects of their immunobiology, including their antigen specificities and the cellular/molecular pathways involved in their development and their mechanisms of action. Furthermore, reduction or dysfunction of the CD25+ CD4+ regulatory T cell population can be responsible for certain autoimmune diseases in humans.

Animals↗
PubMed2003

The role of regulatory T cells in controlling immunologic self-tolerance.

Accumulating evidence indicates that T cell-mediated dominant control of self-reactive T cells contributes to the maintenance of immunologic self-tolerance and its alternation may lead to development of autoimmune disease. Efforts to delineate such a regulatory T cell population have revealed that CD25+ cells within the CD4+ population in normal naive animals including humans possess the regulatory activity. The CD25+CD4+ regulatory T cells are produced by the normal thymus as a functionally distinct subpopulation of T cells. They play critical roles not only in preventing autoimmunity but also in controlling various immune reactions.

Animals↗
PubMed2003

Regulatory T cells in transplantation tolerance.

The identification and characterization of regulatory T (T(Reg)) cells that can control immune responsiveness to alloantigens have opened up exciting opportunities for new therapies in transplantation. After exposure to alloantigens in vivo, alloantigen-specific immunoregulatory activity is enriched in a population of CD4+ T cells that express high levels of CD25. In vivo, common mechanisms seem to underpin the activity of CD4+CD25+ T(Reg) cells in both naive and manipulated hosts. However, the origin, allorecognition properties and molecular basis for the suppressive activity of CD4+CD25+ T(Reg) cells, as well as their relationship to other populations of regulatory cells that exist after transplantation, remain a matter of debate..

Animals↗
PubMed2003

The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery.

Naturally arising CD4+ regulatory T cells, which engage in the maintenance of immunologic self-tolerance, specifically express FOXP3, which encodes a transcription-repressor protein. Genetic defects in FOXP3 cause IPEX, an X-linked autoimmune/inflammatory syndrome. With FOXP3 as a specific marker for regulatory CD4+ T cells in humans, it is now possible to determine their origin and developmental pathway.

Autoimmune Diseases↗
PubMed2003

Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease.

A large body of evidence indicates that T cell-mediated dominant suppression of self-reactive T cells is indispensable for maintaining immunologic unresponsiveness to self-constituents (i.e., self-tolerance) and preventing autoimmune disease. CD25+CD4+ regulatory T cells naturally present in normal animals, in particular, engage in this function, as their reduction or functional abnormality leads to the development of autoimmune disease in otherwise normal animals. They are at least in part produced by the normal thymus as a functionally mature and distinct subpopulation of T cells. Recent studies have demonstrated that CD25+CD4+ regulatory T cells control not only autoimmune reactions but also other immune responses, including tumor immunity, transplantation tolerance and microbial infection. Thus, this unique population of regulatory T cells can be exploited to control pathological as well as physiological immune responses.

Animals↗
PubMed2003

Thymic generation and selection of CD25+CD4+ regulatory T cells: implications of their broad repertoire and high self-reactivity for the maintenance of immunological self-tolerance.

Besides positive and negative selection of T cells, another function of the thymus in maintaining immunological self-tolerance is the production of CD25+CD4+ regulatory T cells capable of preventing autoimmune disease. They acquire the regulatory activity through the thymic selection process, and are released to the periphery as a functionally and phenotypically mature population. Our recent study with transgenic mice in which every class II MHC molecule covalently binds the same single peptide has revealed that a particular self-peptide/MHC ligand in the thymus can positively select a broad repertoire of functionally mature CD25+CD4+ regulatory T cells as well as naive T cells. Interestingly, the regulatory T cells bear higher reactivity than other T cells to the selecting ligand in the thymus even after negative selection by the ligand. This broad repertoire and high self-reactivity of CD25+CD4+ regulatory T cells, together with their high level expression of various accessory molecules, may guarantee their prompt and efficient activation upon encounter with a diverse range of self peptide/MHC complexes in the periphery, ensuring dominant control of self-reactive T cells.

Animals↗
PubMed2003

Regulatory cells in transplantation.

Regulatory T cells can play an important role in both the induction and maintenance of tolerance to donor alloantigens in vivo. Regulatory activity specific for donor alloantingens is enriched amongst CD4+CD25+ T cells in some settings and can be induced by manipulating the immune system before transplantation. Donor alloantigen-specific CD4+CD25+ regulatory T cells can control aggressive CD4+ as well as CD8+ T cells thereby preventing rejection and can mediate linked unresponsiveness. In vivo, donor alloantigen specific CD4+CD25+ cells are dependent on interleukin (IL)10 and CTLA4 for functional activity. These populations of regulatory cells induced by manipulating the adult immune system therefore have properties in common with naturally occurring regulatory T cells. The active regulation/suppression of immune responsiveness to donor alloantigens offers a way to silence aggressive immune responses directed to donor alloantigens thereby preventing damage to the graft from being inflicted. The generation of regulatory T cells with defined alloantigen specificity could provide dynamic control of rejection responses and offers a potential route to permanent graft survival without the need for life-long non-specific immunosuppression.

Animals↗
PubMed2002

Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.

CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gene superfamily--is predominantly expressed on CD25(+)CD4(+) T cells and on CD25(+)CD4(+)CD8(-) thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25(+)CD4(+) T cell-mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.

Animals↗