[Show abstract][Hide abstract] ABSTRACT: Zymosan is a complex fungal component shown to be capable of both promoting and suppressing the development of autoimmune disorders in mice. In this study, we show that a single injection of zymosan just prior to diabetes onset can significantly delay the progression of disease in NOD mice. Zymosan treatment of NOD mice induced the production of biologically active TGF-beta from cells infiltrating the pancreas and was associated with expansion of programmed cell death 1 ligand 1(+)TGF-beta(+) macrophages and Foxp3(+) regulatory T cells in vivo. Neutralization of either TGF-beta or programmed cell death 1 ligand 1 abrogated the protective effects of zymosan. Zymosan acted through TLR2 as well as ERK and p38 MAPK to induce macrophage secretion of TGF-beta and promotion of Foxp3(+) regulatory T cells in vitro and in vivo.
The Journal of Immunology 09/2010; 185(5):2754-62. · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Donor-specific graft tolerance can be established by a combination of allo-antigen exposure and manipulation of T cell function, for example by donor-specific transfusion (DST) under the cover of a non-depleting anti-CD4 mAb. Yet, the cellular basis of this graft tolerance is still obscure. This report shows that T cell-deficient BALB/c nude mice reconstituted with naive unfractionated T cells are specifically tolerized to DBA/2 skin grafts by DST and anti-CD4 mAb treatment, whereas those transferred with T cell suspensions depleted of all Foxp3(+)CD25(+)CD4(+) natural regulatory T cells (Tregs) are not. The treatment inhibits Mls-1(a) allo-antigen-specific expansion of CD4(+) non-Tregs expressing Vbeta6 TCR subfamily but leaves the expansion of Vbeta6-expressing Tregs unaffected, allowing the latter to selectively expand and establish donor-specific tolerance. Furthermore, anti-CD4 mAb inhibits in vitro the selective expansion of allo-antigen-specific CD4(+) non-Tregs but not natural Tregs, as observed with in vitro anti-CD154 [CD40 ligand (CD40L)] mAb or rapamycin treatment. The results collectively indicate that the differential effect of biologicals and pharmacological substances on the expansion of allo-antigen-specific Tregs and effector T cells and resulting dominance of the former can be a key general mechanism underlying dominant transplantation tolerance.
International Immunology 03/2009; 21(4):379-91. · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs-in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells.
[Show abstract][Hide abstract] ABSTRACT: Naturally occurring CD4(+)CD25(+) regulatory T cells (Treg) suppress in vitro the proliferation of other T cells in a cell-contact-dependent manner. Dendritic cells (DCs) appear to be a target of Treg-mediated immune suppression. We show here that, in coculture of dye-labeled Treg cells and CD4(+)CD25(-) naïve T cells in the presence of T cell receptor stimulation, Treg cells, which are more mobile than naïve T cells in vitro, out-compete the latter in aggregating around DCs. Deficiency or blockade of leukocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) abrogates Treg aggregation, whereas that of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (CD152) does not. After forming aggregates, Treg cells specifically down-regulate the expression of CD80/86, but not CD40 or class II MHC, on DCs in both a CTLA-4- and LFA-1-dependent manner. Notably, Treg exerts this CD80/86-down-modulating effect even in the presence of strong DC-maturating stimuli, such as GM-CSF, TNF-alpha, IFN-gamma, type I IFN, and lipopolysaccharide. Taken together, as a possible mechanism of in vitro Treg-mediated cell contact-dependent suppression, we propose that antigen-activated Treg cells exert suppression by two distinct steps: initial LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent LFA-1- and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs. Both steps prevent antigen-reactive naïve T cells from being activated by antigen-presenting DCs, resulting in specific immune suppression and tolerance.
Proceedings of the National Academy of Sciences 07/2008; 105(29):10113-8. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25(+)CD4(+) regulatory T cell (T(R)) assays mainly in activated Foxp3(-) effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25(-)CD4(+) T cells antagonizes T(R)-mediated suppression. Moreover, forced expression of Foxp3 in naive CD25(-) T cells induces constitutive expression of ICER/CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/CREM both in Foxp3 transductants as well as CD25(-) responder T cells suggesting that induction of T(R) function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25(-) responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligand-bearing Foxp3(-) effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T(R) cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/CREM expression in activated CD25(+) Foxp3(-) T cell effectors thus preventing them from producing IL-2.
European Journal of Immunology 05/2007; 37(4):884-95. · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: How regulatory T (TR) cells dampen T cell responses remains unclear. Multiple modes of action have been proposed, including cell contact-dependent and/or cytokine-dependent mechanisms. Suppression may involve direct contact between TR cells and responder T cells. Alternatively, TR cells may act on dendritic cells to reduce their ability to prime T cells by modulating costimulation, inducing the secretion of suppressive cytokines or the increase of tryptophan metabolism. Here, we review emerging, novel mechanisms involved in contact-dependent, TR-mediated suppression of IL-2 production in responder CD25- T lymphocytes and the potential involvement of inducible cAMP early repressor (ICER) in this suppression. Finally, cytokines such as TGF-beta and IL-10, produced by TR cells or other cells, may exert local suppression, which can be conveyed by basic mechanism(s) acting in a similar manner as contact-dependent, TR-mediated suppression.
Journal of Leukocyte Biology 02/2007; 81(1):161-7. · 4.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The debate on whether infection precipitates or prevents autoimmunity remains a contentious one. Recently the suggestion that some unknown microbe can be at the origin of some chronic inflammatory diseases has been countered by accumulating evidence that decreasing infection rates might have an important role to play in the rising prevalence of autoimmune disorders. The 'Hygiene Hypothesis' was initially postulated to explain the inverse correlation between the incidence of infections and the rise of allergic diseases, particularly in the developed world. Latterly, the Hygiene Hypothesis has been extended to also incorporate autoimmune diseases in general. Amongst the various infectious agents, a particular emphasis has been put on the interaction between parasitic worms and humans. Worm parasites have co-evolved with the mammalian immune system for many millions of years and during this time, they have developed extremely effective strategies to modulate and evade host defences and so maintain their evolutionary fitness. It is therefore reasonable to conclude that the human immune system has been shaped by its relationship with parasitic worms and this may be a necessary requirement for maintaining our immunological health. Fully understanding this relationship may lead to novel and effective treatments for a host of deleterious inflammatory reactions.
[Show abstract][Hide abstract] ABSTRACT: Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.
[Show abstract][Hide abstract] ABSTRACT: CD25+CD4+ Regulatory T cells (Treg) represent a unique population of lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data have now confirmed the essential role played by these cells in a host of clinically relevant areas such as self-tolerance, transplantation, allergy and tumor/microbial immunity. Despite this mass of knowledge, significant gaps in our understanding of fundamental Treg biology remain, particularly regarding their development and mechanisms of suppression. In this review we attempt to highlight the current controversies and directions in which this exciting field is moving.
International Immunology 08/2006; 18(7):991-1000. · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin-2 (IL-2) is a well-known T-cell growth factor, which is traditionally implicated in the agonistic stimulation of immune responses. Recent work, however, has uncovered an unexpected function of this cytokine. In particular, IL-2 appears crucial to maintaining peripheral tolerance by supporting the survival and function of CD25+ CD4+ regulatory T cells. A recent study examining the role of IL-2 in the peripheral generation of regulatory T cells from apparently naïve T cells has gone some way to reconciling the seemingly opposing functions of this cytokine.
Trends in Immunology 04/2006; 27(3):109-11. · 12.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of type 1 diabetes in nonobese diabetic (NOD) mice is influenced by major histocompatibility complex (MHC) class II genes. The NOD-E transgenic mouse, which expresses H2-E as a result of the introduction of an Ead gene, is protected from development of type 1 diabetes. While the mechanism of protection remains unclear, the effect has been regarded as a model system for MHC protection from autoimmunity. We have investigated the effect of deletions of the Ea promoter region, which, in turn, affect H2-E expression patterns in transgenic NOD mice. We have constructed transgenic NOD mice where the X (DeltaX) and Y (DeltaY) boxes of the Ead gene have, respectively, been functionally deleted. Previous reports, using X- or Y-box-deleted H2-E transgenic mice, made by crossing the appropriate transgenes onto the NOD background from C57BL/6 transgenic mice, indicated that promoter mutation abrogated the H2-E-mediated protection seen in NOD-E. The NOD DeltaX and NOD DeltaY transgenic mice generated in the present study differ in susceptibility to diabetes from wild-type NOD mice. NOD DeltaY1 animals are protected from diabetes development, while DeltaX mice remain susceptible, albeit to a lesser extent than the parental NOD strain.
Scandinavian Journal of Immunology 02/2006; 63(1):17-25. · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CD4(+) regulatory T (T(R)) cells represent a unique lineage of thymically generated lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data has now confirmed the key role played by these cells in the maintenance of self-tolerance. Increasingly, the importance of these cells is also being recognized in a host of other clinically relevant areas such as transplantation, tumour immunity, allergy and microbial immunity. Additionally, it is also possible to generate T(R) cells by using a variety of ex vivo experimental approaches. We will focus here on harnessing the suppressive abilities of both these families of regulatory cells and how this should give us access to a potent cell-based immunotherapy appropriate for clinical application.
Philosophical Transactions of The Royal Society B Biological Sciences 10/2005; 360(1461):1647-61. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Naturally occurring CD4+CD25+ regulatory T (TR) cells play crucial roles in normal immunohomeostasis. CD4+CD25+ TR cells exhibit a number of interesting in vitro properties including a 'default state' of profound anergy refractory to conventional T cell stimuli. We investigated the in vitro activation requirements of CD4+CD25+ TR cells using bone marrow-derived DC, which as professional antigen presenting cells (APC) can support the activation of normal naive T cells. Comparison of different APC types revealed that LPS-matured DC were by far the most effective at breaking CD4+CD25+ TR cell anergy and triggering proliferation, and importantly their IL-2 production. Examination of Foxp3, a key control gene for CD4+CD25+ TR cells, showed this to be stably expressed even during active proliferation. Although CD4+CD25+ TR cell proliferation was equivalent to that of CD25- cells their IL-2 production was considerably less. Use of IL-2-/- mice demonstrated that the DC stimulatory ability was not dependent on IL-2 production; nor did IL-15 appear crucial but was, at least in part, related to costimulation. DC also blocked normal CD4+CD25+ TR cell-mediated suppression partially via IL-6 secretion. DC therefore possess novel mechanisms to control the suppressive ability, expansion and/or differentiation of CD4+CD25+ TR cells in vivo.
International Immunology 01/2005; 16(12):1769-80. · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Clinical Investigation 12/2004; 114(9):1209-17. · 13.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The essential role played by CD25(+)CD4(+) regulatory T cells (T(R) cells) in the control of physiological as well as pathological immunity is now well established, but many aspects of their biology still remain unclear. One of the unresolved issues regards their development: where does this occur, what signals are required, and how do T(R) cells fit into the larger taxonomy of the T-cell family? Recent data has begun to shed light on the development and function of these important cells.
Current Opinion in Immunology 05/2004; 16(2):203-8. · 7.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Arthritis research & therapy 02/2004; 6(1):19-25. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Infection with Schistosoma mansoni (S. mansoni) or exposure to eggs from this helminth inhibits the development of type 1 diabetes in NOD mice. In this study we show that soluble extracts of S. mansoni worm or egg completely prevent onset of type 1 diabetes in these mice but only if injection is started at 4 weeks of age. T cells from diabetes-protected mice make IL-10 in recall responses to parasite antigens. These cells are furthermore impaired in their ability to transfer diabetes to NOD-SCID recipients. Bone marrow dendritic cells derived from NOD mice are found to make more IL-10 and less IL-12 following culture with S. mansoni soluble egg antigens in conjunction with lipopolysaccharides. NOD mice are deficient in NKT cells. Soluble worm and egg antigens increase the numbers of V alpha 14i NKT cells in NOD mice. These effects of schistosome antigens on the innate immune system provide a mechanism for their ability to prevent type 1 diabetes in NOD mice.
European Journal of Immunology 06/2003; 33(5):1439-49. · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Experimental autoimmune thyroiditis (EAT) is inducible in mice by immunization with mouse thyroglobulin (mTg) together with adjuvant, either lipopolysaccharide (LPS) or complete Freund's adjuvant (CFA). The severity of the disease is dependent on the mouse strain and on the adjuvant used. We have previously shown that interleukin (IL)-12 deficient C57BL/6 mice immunized with mTg and CFA develop a significantly less severe thyroid infiltration in comparison to wild type C57 BL/6 mice. This result indicated a pivotal role for IL-12 in the development of thyroiditis induced with CFA and mTg. In the present study we demonstrate that IL-12 deficiency does not impair EAT induction when LPS is used as adjuvant. We also demonstrate that peritoneal exudate cells from IL-12-deficient mice stimulated in vitro either with LPS or IL-18 secrete high levels of tumour necrosis factor (TNF). Together the results emphasize the difference between the use of CFA and LPS in the induction of EAT, the importance of TNF-alpha for the pathogenesis of LPS-induced EAT, and also show the capacity of IL-12-deficient mice to develop a competent response to LPS.