Dominant Tolerance Research Articles

Inhibition of γδ T Cell Proliferation by CD4+CD25+FOXP3+ Regulatory T Cells (Treg).

CD4+CD25+FOXP3+ regulatory T cells (Treg) are a unique population of T cells that maintain immune tolerance by suppressing self-reactive cells. Treg also contribute to the establishment of a dominant tolerance during infections and after allogeneic transplantation and suppress immune response to tumors. Increasing evidence supports the existence of elevated numbers of Treg in both solid tumors and hematological malignancies. In this study we show that Treg may also suppress other arms of an effective immune response. In vitro, purified human CD4+CD25+FOXP3+ Treg (by immunomagnetic selection) directly inhibit phosphoantigen (BrHPP)-mediated proliferation of Vγ9Vδ2 T cells, the major γδ T lymphocyte subset in humans. Importantly, suppression of γδ T cell proliferation by Treg was maintained when Treg where separated from γδ T cells by Transwells, suggesting that the inhibitory function of Treg on γδ T cell proliferation is not cell-contact independent and rather soluble factors produced by Treg contribute to this suppressive effect. However, Treg do neither influence the expression of activation markers (CD69, CD25) nor the production of IFN-γ by Vγ9Vδ2 T cells stimulated with phosphoantigen indicating that not all effector functions of Vγ9Vδ2 T cells are suppressed by Treg. As we have recently reported, phosphoantigen-mediated γδ T cell proliferation is frequently suppressed in cancer patients. This observation prompted us to address the role of Treg in controlling γδ T cell proliferation in cancer patients. An inverse correlation between Treg frequencies (i.e. the ratio between Treg and Vγ9Vδ2 T cells) in peripheral blood and phosphoantigen-mediated γδ T cell proliferation was found (mean Treg/Vγ9Vδ2 T cell ratio in cancer patients with maintained phosphoantigen-mediated γδ T cell proliferation (n=14): 4.06; mean Treg/Vγ9Vδ2 T cell ratio in cancer patients without phosphoantigen-mediated γδ T cell proliferation (n=55): 33.36)). Therefore, the Treg/Vγ9Vδ2 T cell ratio in peripheral blood can predict the capacity of γδ T cells to proliferate in response to phosphoantigens. In conclusion, these findings support a role for Treg in blunting the γδ T cell arm of the innate immune response in cancer patients and highlight the potential of Treg depletion (e.g. by anti-CD25 antibodies, cyclophosphamide or fludarabine) to promote γδ T cell mediated antitumor activity.

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Regulatory T cells in microbial infection

Natural T regulatory cells (NatTReg) limit immunopathology and protective immune responses induced upon microbial infection. In addition, infection increases the number and activity of NatTReg. These findings need to be conciliated with the process of 'self-nonself' discrimination based on the function of NatTReg committed intrathymically and positively selected (and activated) on thymic epithelial cells. A review of the available evidence comforts the assumptions that, in physiological conditions, NatTReg engaged in the immune responses to microbial infections are drawn from the autoreactive repertoire even if some may appear to be microbe specific. This contention also provides a suitable explanation for the 'hygiene hypothesis': infections re-enforce the physiological mechanisms of natural dominant tolerance, through the expansion of naturally occurring regulatory T cells. Accumulating evidence demonstrates that pro-inflammatory ligands of Toll-like receptors expressed by NatTReg, both of microbial (e.g., lipopolysaccharide, flagellin, peptidoglycans) and endogenous (e.g., stress proteins and degradation products of the extracellular matrix) origin, may play a critical role in their activation and expansion. As NatTReg vigorously respond to IL-2/IL-15 locally produced by ongoing effector responses, this whole set of mechanisms provides for a robust feedback process that limits tissue damage and accounts for an 'organism-centered' quality control of immune responses. Detailed knowledge on these molecular and cellular bases should open novel opportunities for intervention in a variety of critical conditions, such as autoimmunity, allergy, chronic infections, and cancer, for which we currently lack effective therapies.

Regulatory T Cells Reversibly Suppress Cytotoxic T Cell Function Independent of Effector Differentiation

Mechanisms of dominant tolerance have evolved within the mammalian immune system to prevent inappropriate immune responses. CD4(+)CD25(+) regulatory T (T(reg)) cells have emerged as central constituents of this suppressive activity. By using multiphoton intravital microscopy in lymph nodes (LNs) of anesthetized mice, we have analyzed how cytotoxic T lymphocytes (CTLs) interact with antigen-presenting target cells in the presence or absence of activated T(reg) cells. Nonregulated CTLs killed their targets at a 6.6-fold faster rate than regulated CTLs. In spite of this compromised effector activity, regulated CTLs exhibited no defect in proliferation, induction of cytotoxic effector molecules and secretory granules, in situ motility, or ability to form antigen-dependent conjugates with target cells. Only granule exocytosis by CTLs was markedly impaired in the presence of T(reg) cells. This selective form of regulation did not require prolonged contact between CTLs and T(reg) cells but depended on CTL responsiveness to transforming growth factor-beta. CTLs quickly regained full killing capacity in LNs upon selective removal of T(reg) cells. Thus, T(reg) cells reversibly suppress CTL-mediated immunity by allowing acquisition of full effector potential but withholding the license to kill.

Cutting Edge: Allogeneic CD4+CD25+Foxp3+ T Regulatory Cells Suppress Autoimmunity while Establishing Transplantation Tolerance

An important unresolved question with regard to T regulatory (Treg) cell specificity and suppressive activity is whether allogeneic Treg cells inhibit self-reactive T cells. In the present study, this issue was addressed using IL-2Rbeta-deficient mice that develop rapid lethal autoimmunity due to impaired production of Treg cells. We show that adoptive transfer of completely MHC-mismatched Treg cells into IL-2Rbeta(-/-) mice resulted in life-long engraftment of the donor cells, which exhibited skewed reactivity toward host alloantigens, and prevented autoimmunity. Thus, Treg cells that underwent thymic selection by peptide/MHC class II complexes distinct from those recognized by autoreactive T cells, still effectively suppress autoimmunity. Remarkably, when such animals were skin grafted, they exhibited dominant tolerance to those grafts bearing MHC molecules that were shared with donor Treg cells. Collectively, these data demonstrate that effective engraftment by allogeneic Treg cells controls autoimmunity and results in permissive conditions for long-term acceptance of allografts.

Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs

Safe induction of autoantigen-specific long-term tolerance is the "holy grail" for the treatment of autoimmune diseases. In animal models of type 1 diabetes, oral or i.n. immunization with islet antigens induces Tregs that are capable of bystander suppression. However, such interventions are only effective early in the prediabetic phase. Here, we demonstrate that a novel combination treatment with anti-CD3epsilon-specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with monotherapy with anti-CD3 or antigen alone. In vivo, expansion of CD25(+)Foxp3(+) and insulin-specific Tregs producing IL-10, TGF-beta, and IL-4 was strongly enhanced. These cells could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CD8 responses. Thus, combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.

Dominant Tolerance to Kidney Allografts Induced by Anti-Donor MHC Class II Antibodies: Cooperation between T and Non-T CD103+ Cells

Allograft acceptance can be induced in the rat by pretransplant infusion of donor blood or spleen cells. Although promoting long-term acceptance, this treatment is also associated with chronic rejection. In this study, we show that a single administration of anti-donor MHC class II alloimmune serum on the day of transplantation results in indefinite survival of a MHC-mismatched kidney graft. Long-term recipients accept a donor-type skin graft and display no histological evidence of chronic rejection. The kidney grafts of tolerant animals display an accumulation of TCR Cbeta, FoxP3, and IDO transcripts. Moreover, as compared with syngeneic recipients, tolerant recipients harbor a large infiltrate of MHC class II(+) cells and CD103(+) cells. In vitro, splenocytes from tolerant recipients exhibit decreased donor-specific proliferation, which is restored by depletion of non-T cells and partially restored by the blockade of IDO. Finally, splenocytes from tolerant recipients, but not purified T cell splenocytes, transfer donor-specific infectious tolerance without chronic rejection, after infusion into naive recipients, over two generations. However, splenocytes depleted of T cells or splenocytes depleted of CD103(+) cells fail to transfer tolerance. Collectively, these data show that a single administration of anti-donor MHC class II alloimmune serum induces a tolerant state characterized by an infiltration of the kidney graft by regulatory T cells and CD103(+) cells. These data also show that the transfer of tolerance requires the presence of both T cells and CD103(+) dendritic cells. The precise mechanism of cooperation of these two cell subsets remains to be defined.

Genetic analysis of toxic aluminum ion tolerance in barley

The genetic control of high tolerance of toxic aluminum ions in barley Hordeum vulgare L. has been studied. Cultivar Faust I (c-24612) and accession c9736 from Karelia have been compared with aluminum-sensitive cv. Colsess IV (accession c-24626). Analysis of F1, F2BC1, F3, and F4 progenies has shown that the development of roots of cv. Faust I in water medium with aluminum ions is determined by one (AlpF1) or two (AlpF1 and AlpF2) genes. The development of roots of accession c9736 is determined by two genes, AlpK1 and AlpK2. The genes have not been not tested for nonidentity. The high tolerance of Faust I shoots are determined by one major tolerance factor and one dominant inhibitor gene, which hampers the manifestation of the dominant tolerance gene. The penetrance of the inhibitor gene may be incomplete. The aluminum sensitivity of roots and 7-day shoots of cv. Faust I is determined by different genetic factors. The response of barley plants to aluminum ions may be determined by small-effect genes.

Costimulation Blockade of Both Inducible Costimulator and CD40 Ligand Induces Dominant Tolerance to Islet Allografts and Prevents Spontaneous Autoimmune Diabetes in the NOD Mouse

Costimulation blockade is a promising strategy for preventing allograft rejection and inducing tolerance. Using a fully allogeneic mouse model, we tested the effectiveness of the combined blockade of the CD40 ligand and the inducible costimulator (ICOS) on islet allograft survival and in the prevention of autoimmune diabetes in the NOD mouse. Recipients treated with blocking monoclonal antibodies (mAbs) to ICOS and the CD40 ligand had significant prolongation of graft survival, with 26 of 28 functioning for >200 days. Long-term engrafted mice maintained antidonor proliferative and cytotoxic responses, but donor-specific immunization did not induce graft rejection, and challenge with second, same donor but not third-party grafts resulted in long-term acceptance. The immunohistology of tolerant grafts demonstrated the presence of CD4+CD25+ T-cells expressing Foxp3, and islet/kidney composite grafts from tolerant mice, but not from mice lacking lymphocytes, were accepted indefinitely when transplanted into naïve B6 mice, suggesting that recipient T-cells were necessary to generate dominant tolerance. Combined anti-ICOS and anti–CD40 ligand mAb therapy also prevented diabetes in NOD mice, with only 11% of treated recipients developing diabetes compared with 75% of controls. These data demonstrate that the blockade of CD40 ligand and ICOS signaling induces islet allograft tolerance involving a dominant mechanism associated with intragraft regulatory cells and prevents autoimmune diabetes in NOD mice.

Modulation of Graft-versus-Host Disease: Role of Regulatory T Lymphocytes

Graft-versus-host (GVH) disease (GVHD) continues to be a major life-threatening complication after allogeneic bone marrow transplantation. Considerable progress has been made elucidating the pathophysiology of acute GVHD. Mature donor T cells transferred along with the marrow graft directly recognize antigenic differences on antigen-presenting cells of the host. Once activated, donor antihost-specific T cells can mediate tissue destruction. Interestingly, the failure to clonally delete autoreactive T cells in the thymus can also lead to an autoimmune syndrome mimicking the pathology of GVHD. Negative selection in the thymus may be compromised either by damage to the thymic epithelium (because of a direct attack by donor antihost alloreactive T cells) or by the use of immunosuppressive drugs that inhibit clonal deletion. An important component underlying GVHD mediated by either alloreactive or autoreactive T cells is the absence of a competent peripheral regulatory system. Studies in animal model systems clearly indicate that regulatory T cells play a vital role in down-regulating GVHD and are critically important for the establishment of active dominant tolerance to both allo- and self-major histocompatibility complex antigens. Although multiple populations of cells appear to participate in this process, CD4 + regulatory T cells that innately express CD25 + appear to orchestrate the regulatory control of the immune response. Evidence for regulatory T cells in clinical bone marrow transplantation, however, remains rudimentary. The recent identification that CD4 +CD25 + regulatory T cells preferentially express the Foxp3 nuclear transcription factor and the development of molecular reagents to isolate antigen-specific T cells have provided unique opportunities to explore immunoregulatory mechanisms after clinical marrow transplantation. Recent studies in recipients of clinical bone marrow transplantation suggest that antigen-specific CD4 +CD25 +Foxp3 + T cells play a vital role in the regulatory control of GVH reactions mediated by both alloreactive and autoreactive lymphocytes. These regulatory T cells also appear to facilitate the establishment of donor antihost and donor antidonor (self) tolerance.

Costimulation Blockade of Both Inducible Costimulator and CD40 Ligand Induces Dominant Tolerance to Islet Allografts and Prevents Spontaneous Autoimmune Diabetes in the NOD Mouse

Costimulation blockade is a promising strategy for preventing allograft rejection and inducing tolerance. Using a fully allogeneic mouse model, we tested the effectiveness of the combined blockade of the CD40 ligand and the inducible costimulator (ICOS) on islet allograft survival and in the prevention of autoimmune diabetes in the NOD mouse. Recipients treated with blocking monoclonal antibodies (mAbs) to ICOS and the CD40 ligand had significant prolongation of graft survival, with 26 of 28 functioning for >200 days. Long-term engrafted mice maintained antidonor proliferative and cytotoxic responses, but donor-specific immunization did not induce graft rejection, and challenge with second, same donor but not third-party grafts resulted in long-term acceptance. The immunohistology of tolerant grafts demonstrated the presence of CD4(+)CD25(+) T-cells expressing Foxp3, and islet/kidney composite grafts from tolerant mice, but not from mice lacking lymphocytes, were accepted indefinitely when transplanted into naïve B6 mice, suggesting that recipient T-cells were necessary to generate dominant tolerance. Combined anti-ICOS and anti-CD40 ligand mAb therapy also prevented diabetes in NOD mice, with only 11% of treated recipients developing diabetes compared with 75% of controls. These data demonstrate that the blockade of CD40 ligand and ICOS signaling induces islet allograft tolerance involving a dominant mechanism associated with intragraft regulatory cells and prevents autoimmune diabetes in NOD mice.

Therapeutic Cancer Vaccines: At Midway Between Immunology and Pharmacology

The pursuit of active specific immunotherapy of cancer re-emerged vigorously in the 90s. More than 50 vaccines are currently under clinical testing, and more than 400 clinical trials have been conducted. This wave of enthusiasm is rooted in fundamental immunology, as new paradigms, such as the dominant tolerance through T-regulatory cells and the instructive role of the innate immune system on the adaptive immune system, opened the possibility that an efficient cancer vaccination could be achieved even without the need of cancer neoantigens, provided that antigen presentation could be increased, and that regulatory circuits could be controlled. However, recent failures in some large trials have brought disappointment and have highlighted the differences between experiments in young, healthy mice with small transplanted tumours, and clinical testing in aged, ill patients with advanced spontaneous tumours, driving the attention to issues such as tumour editing, tumour-induced immunosuppression, and immunosenescence. The molecular basis of these phenomena is only partially known. Additionally, the inherent complexity of the immune system as a network of multiple interactions and redundant control loops among a huge diversity of components sets another barrier to the translation of in vitro reductionist knowledge into rationally designed clinical trials. All this calls for a new therapeutic paradigm in cancer vaccines, moving beyond the analogy with the classic drug-target approach, and targeting the immune system regulation as a whole, and its interaction with the tumour, in all its complexity. Early mathematical modelling of cancer immunotherapy has suggested how to go about it. This re-evaluation of the cancer vaccine landscape, suggests that future successful cancer immunotherapy will be combined immunotherapy, will be exquisitely schedule-dependent and will need new experimental models allowing for the exploration of the mechanisms of resistance and tumour escape, such as tumour editing and tumour induced immunosuppression, in the context of the physiology of the immune system of the elderly. These shifts will put cancer vaccines closer to pharmacology than to conventional preventive vaccinology, or at least at the midway. A change in the design and the ultimate goals of the clinical trials will also be needed, identifying long term stabilization of the disease and quality of life as main endpoints, again closer to the clinical management of most chronic noncommunicable diseases.

Low temperature responses of Nothofagus dombeyi and Nothofagus nitida, two evergreen species from south central Chile

Nothofagus dombeyi (Mirb.) Blume and Nothofagus nitida (Phil.) Krasser are closely related evergreen trees native to south central Chile. Nothofagus dombeyi is a pioneer in habitats subject to high daytime irradiances and nighttime freezing temperatures and has a wider altitudinal and latitudinal distribution than N. nitida, which is restricted to more oceanic climates. We postulated that N. dombeyi has a greater cold-acclimation capacity, expressed as a greater capacity to maintain a functional photosynthetic apparatus at low temperatures, than N. nitida. Because cold-acclimation may be related to the accumulation of cryoprotective substances, we investigated relationships between ice nucleation temperature (IN), freezing temperature (FT), and the temperature causing injury to 50% of the leaf tissues (LT(50)) on the one hand, and concentrations of total soluble carbohydrates (TSC), starch and proline on the other hand. Observations were made throughout a seasonal cycle in adults and seedlings in the field and in seedlings in the laboratory under cold-acclimation inductive and non-inductive conditions. In adults, LT(50) values were lower in N. dombeyi than in N. nitida, suggesting that N. dombeyi is the more frost tolerant species. Adults of both species tolerated freezing in autumn and winter but not in spring and summer. In the fall and winter, seedlings of N. dombeyi had a much lower LT(50) than those of N. nitida. Nothofagus nitida seedlings, in autumn and winter, exhibited freezing avoidance mechanisms. Although elevated TSC and proline concentrations may contribute to freezing tolerance in adults of both species, an increase in proline concentration is unlikely to be the dominant frost tolerance response in adults because proline concentrations were higher in N. nitida than in N. dombeyi. In seedlings, however, there were large differences in proline accumulation between species that may account for the difference between them in freezing tolerance. Starch concentration in both species decreased during winter. Chlorophyll fluorescence indicated that maximal photochemical efficiency (F(v)/F(m)) remained at optimal values (~0.8) throughout the year. The effective photochemical efficiency of PSII (PhiPSII) and relative electron transport rates (ETR(r)) decreased in winter in both species. In seedlings, fluorescence parameters were more affected in winter in N. nitida than in N. dombeyi. We concluded that adults and seedlings of N. dombeyi are hardier than adults and seedlings of N. nitida, which is consistent with its wider latitudinal and altitudinal distribution.

A function for interleukin 2 in Foxp3-expressing regulatory T cells

Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.

Mechanisms of inducible resistance against Bacillus thuringiensis endotoxins in invertebrates

Abstract Resistance in insect pests against the endotoxin of Bacillus thuringiensis (Berliner) (Bt) is a major threat to the usefulness of this biopesticide, both used as traditional formulations and in transgenic crops. A crucial requirement for the development of successful resistance management strategies is a molecular understanding of the nature and inheritance of resistance mechanisms. This information can be used to design management strategies that will delay or counteract Bt resistance. The best known Bt resistance mechanism is inactivation of brush border membrane receptors. This type of resistance has a largely recessive mode of inheritance, which has enabled the design of resistance management approaches involving high dose and refuge strategies. Recent observations suggest that other resistance mechanisms are possible, including a mechanism that sequesters the toxin in the gut lumen through inducible immune reactions. The elevated immune status associated with tolerance to the toxin can be transmitted to subsequent generations by a maternal effect, which has implications for resistance management in the field. The high dose/refuge strategy may not be appropriate for the management of these alternative resistance mechanisms and other strategies have to be developed if inducible dominant resistance or tolerance mechanisms occur frequently in the field.

Foxp3 and dominant tolerance

The hallmark of the adaptive immune system is the random generation of antigen receptors in developing lymphocyte clones through a process of somatic cell gene rearrangement mediated by the recombination-activating gene recombinase. The essentially unlimited specificities of this anticipatory

A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3

The random generation of antigen receptors in developing lymphocytes results in a considerable risk of autoimmunity. Regulatory T cells (T(reg) cells) act in a dominant, trans-acting way to actively suppress immune activation and maintain immune tolerance. Here, we discuss the principal advances in our understanding of the molecular mechanisms of T(reg) cell development and function with particular emphasis on the forkhead transcription factor Foxp3. Accumulating evidence suggests that T(reg) cells represent a dedicated T cell lineage and that Foxp3 functions as the T(reg) cell lineage specification factor. The aggressive early-onset lymphoproliferative syndrome resulting from Foxp3 deficiency identifies T(reg) cells as vital mediators of immunological tolerance to self and Foxp3 as the mediator of the genetic mechanism of dominant tolerance.

Natural regulatory T cells and self-tolerance

The adaptive immune system allows individual organisms to mount defensive reactions against unanticipated pathogens by developmentally creating a diverse repertoire of clonally distributed receptors capable of recognizing a multitude of antigens and then expanding as effector cell populations those that can recognize molecules from the pathogens. To function properly, the system must deal with the problem of randomly generated receptors that can recognize self components. Most solutions to this self-tolerance problem are cell intrinsic and involve the deletion or inactivation of autoreactive cells. However, an extrinsic form of dominant tolerance has been demonstrated that takes the form of CD4(+) regulatory T cells. This perspective discusses why such a mechanism might have evolved and the problems it presents for self-non-self discrimination.

The Generation of CD25+CD4+ Regulatory T Cells That Prevent Allograft Rejection Does Not Compromise Immunity to a Viral Pathogen

In all but a small minority of cases, continued survival of solid organ grafts after transplantation depends on lifelong, nonselective immunosuppression that, although effective, results in increased rates of infection, cancer, and vascular disease. Therapeutic strategies that engage or mimic self-tolerance may allow prolonged allograft survival without the disadvantages of nonspecific immunotherapy. Pretreatment of recipient mice with donor alloantigen combined with transient modulation of the peripheral T cell pool with anti-CD4 Ab leads to the indefinite survival of MHC-incompatible cardiac allografts without further therapy. Tolerance is dependent on CD25+ CD4+ regulatory T cells that arise from naive CD25- precursors and regulate rejection via both IL-10 and CTLA-4. Although these cells are clearly effective at controlling rejection, the proven ability of recently activated CD25+ cells to mediate bystander regulation raises the possibility that tolerized individuals might also have a reduced capacity to respond to environmental pathogens. We have examined anti-influenza responses in tolerized primary heart recipients, secondary recipients following adoptive transfer of regulatory populations, and tolerized mice in which bystander regulation has been deliberately induced. Neither virus-specific CTL activity in vitro nor the clearance of virus in vivo was significantly diminished in any of these treatment groups compared with infected unmanipulated controls. The data suggest that the induction of dominant allograft tolerance dependent on regulatory T cells does not necessarily result in attenuated responses to pathogens providing further support for the development of tolerance induction protocols in clinical transplantation.

Regulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3

Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions.