[Frontiers in Bioscience 14, 333-343, January 1, 2009]
Natural Tregs and autoimmunity
Department of Medicine, University of California Los Angeles, 1000 Veteran Avenue 32-59, Los Angeles, California 90095-1670
TABLE OF CONTENTS
1. ABSTRACT
The subset of CD4+ T lymphocytes that coexpress high levels of the interleukin (IL)-2 a receptor and the transcription factor Foxp3 (CD4+CD25highFoxp3+ cells), commonly called regulatory T cells (Tregs), have a key role in the mechanisms of peripheral immune tolerance. Tregs modulate innate and adaptive immune responses in vitro and in vivo by suppressing the proliferation and cytokine production in different subsets of immune cells. Their key role in autoimmunity is suggested by the finding that reconstitution of normal numbers and/or function of Tregs in autoimmune animals associates with a delay of disease development and progression, whereas the elimination of Tregs can anticipate or precipitate disease. Since naturally occurring ("natural") Tregs represent only a small fraction of peripheral blood cells, the investigations for possible therapeutic use of Tregs in autoimmunity has largely focused on the use of "adaptive" Tregs, which can be induced through several different modalities. This review discusses the role of natural Tregs in the suppression of autoimmune responses and the relevance of these cells for possible therapeutic applications in autoimmunity.
2. INTRODUCTION
Two arms of the immune system act in concert to fight the challenges that come from the environment (i.e. pathogens) and/or from the host itself (i.e. transformed cells). One arm is the innate immunity - a first-line, primordial defense against bacterial or viral pathogens. The other arm is the adaptive immunity, which provides a somehow delayed, yet more efficient and specific response. While the innate immune system lacks a fine specificity in lieu of a broader recognition of common features shared by many pathogens, the adaptive immune system typically employs cells that have a defined antigenic specificity. Because of the vast number of epitopes that can be encountered - and their possible structural similarity with self antigens - the adaptive immune system carries an intrinsic risk for generating autoreactive cells potentially capable to trigger autoimmune responses (1-2). To limit this risk, one mechanism to keep self-reactive lymphocytes under control is immune tolerance, which helps to avert autoimmunity by preventing and/or shifting potentially deleterious autoreactive immune response towards non-injurious immune responses. Immune tolerance operates at a central level (i.e. thymus, bone marrow) and in the periphery, through mechanisms that include the deletion of potentially pathogenic clones, the hyporesponsiveness to antigenic stimulation (anergy), an ignorance for the antigen, and the suppression of immune responses by regulatory cells.
Regulatory/suppressor cells are phenotypically heterogeneous and include subsets of CD4+ T cells (see below) but also natural killer (NK) and NK T (NKT) cells, CD4-CD8- T cells, CD8 cells (CD8+CD28-, CD8+CD122+, CD8+CD25+ and Qa-1-restricted CD8+ T cells), dendritic cells (DC), B cells, and gd T cells (3-10). The mechanism of action of each of these immunoregulatory cell populations may be specific for a subset or common to other subsets, i.e. the secretion of transforming growth factor (TGF)-b and interleukin (IL)-10 can have a central role in the suppressive activity of Tr1 cells (see below) and NKT cells (5), while natural Tregs need a cell-to-cell contact to exert their suppression on target cells (see below). Aspects such as the interplay between Tregs and DC have been reviewed elsewhere (11).
In general, Tregs can be important in suppressing autoimmune reactivity but can be deleterious in tumor immune surveillance because of their capacity to suppress the activation, proliferation, and effector function of tumor-infiltrating T-cells (12-13). Analogous considerations on possible undesired effects of the Tregs can be made in regard to the capacity of these cells to suppress the effector function of immune cells reactive to pathogens in infection (as considered at the end of the chapter).
3. REGULATORY T CELLS (TREGS)
As schematically shown in figure 1, naïve CD4+ T cells can differentiate towards T helper (Th)1, Th2, Th17, and regulatory T cells (Tregs), both in vitro and in vivo, depending on the type of stimulation, antigen concentration, co-stimulation, and cytokine milieu where the immune response takes place (14-15). In general, the presence of interleukin (IL)-12 skews the CD4+ T cells towards a Th1 phenotype, IL-4 towards Th2, TGF-b (+/- IL-2) towards Tregs, and IL-6 and TGF-b towards Th17 - with possible mutually exclusive skewing between Tregs and Th17 phenotypes (16). The committed cells typically express specific transcription factors: T-bet for Th1, GATA-3 for Th2, Foxp3 for Tregs, and RORgt for Th17 cells (17-22).
The best characterized subsets of CD4+ T cells with immune suppressive capacity described so far are the T-regulatory 1 (Tr1) cells (23), the Th3 cells (24), and the CD4+CD25+ T cells (25-26).
Tr1 cells are IL-10 producing CD4+ regulatory T cells induced from CD4+ T cells by repetitive antigenic stimulation in the presence of IL-10 (23) or immature DC (27). Tr1 cells produce high levels of IL-10 and can be generated by chronic activation in the presence of IL-10, both in humans and in mice (23, 28).
Th3 regulatory T cells are TGF-b-producing CD4+ T cells that suppress CD4+ T cells in an antigen-nonspecific manner (24). These cells secrete TGF-b, IL-4 and IL-10 (29), and can be induced in vitro after exposure of CD4+CD25- T cells to TGF-b or in vivo following oral or intravenous administration of antigen (30). The suppressive effect of ex vivo-induced Th3 cells appears mediated by suppressive cytokines and is thus, at least in part, cell-contact independent (30-31).
Finally, the most widely studied and best characterized regulatory CD4+ T cells are the CD4+CD25+ T cells. In organ-specific autoimmunity, a deficiency of Tregs typically associates with development of organ damage (32-34), and a restoration of the number and/or function of Tregs confers protection from autoimmunity (33-37). In systemic autoimmunity, Treg-depleted animals typically develop multi-organ autoimmune disease (38), while supplementation of syngeneic Tregs or adoptive transfer of in vitro expanded Tregs abrogates the development of autoimmune disease manifestations (39).
3.1. Types of Tregs
CD4+ regulatory T cells can be schematically divided into two groups: naturally occurring ("natural") Tregs, and induced ("adaptive") Tregs.
3.1.1. Natural Tregs
Natural Tregs arise from the thymus during ontogeny and, in the mouse, they seed the periphery around day 3 of neonatal life (40-41, 17). The number of natural Tregs circulating in the peripheral blood of adult mice remains virtually constant throughout life, comprising 5-10% of the CD4+ cells. The fraction of Tregs is smaller in humans, where they represent the 1% to 2% of total CD4+ T cells, e.g. the ones with highest CD25 expression (CD25high) (42).
Natural Tregs constitutively express CD4, CD25 and Foxp3, and suppress the proliferation and cytokine production of target cells in vitro and in vivo. These cells contribute to avert autoimmune disease by suppressing activated immune cells through cell contact-dependent and cytokine-independent mechanisms (43-45). The cell-to-cell contact suppressive mechanisms used by Tregs include cytotoxic functions involving the synthesis of perforin, CD18, and granzyme A in a Fas-independent manner (46). The targets of the cytotoxic activity of the Tregs include CD4+CD25- T cells, CD8+ T cells, monocytes, antigen-presenting B cells, and DC (46-47, 25-26). A role for lymphocyte activation gene 3 (LAG-3) in the cell-to-cell mediated suppression of natural Tregs has been suggested by the blockade of the suppressive function of these cells using anti-LAG-3 antibody in vitro and in vivo, and by the finding that transduction of LAG-3 into CD4+CD25− T cells conveys a suppressive function to these cells (48). Also, natural Tregs may require the ligation of B7 molecules on target T cells to mediate suppression of conventional T cells, since target cells deficient in B7 molecules (CD80 and, to a lesser degree, CD86) are resistant to Treg suppression (49).
Although anergic in vitro, natural Tregs can be expanded ex vivo and retain their functional suppressive activity when stimulated with anti-CD3 and IL-2 or when cultured with high ratios of antigen-loaded DC (50-51). Another mean to expand natural Tregs and increase their survival is through the combination of anti-CD3 and anti-CD28 antibodies (52).
Interestingly, CD4+CD25+ Tregs can promote infectious tolerance - a phenomenon by which they can induce conventional CD4+ T cells to also become suppressor cells (53). The capacity of natural Tregs to amplify immune regulatory responses is shared with adaptive Tregs induced ex vivo using TGF-b and IL-2, as these cells can also "infectiously" tolerize CD4+CD25− cells to become suppressor cells (54).
3.1.2. Adaptive Tregs
Adaptive Tregs can be generated in cultures or in the periphery. For example, CD4+CD25+Foxp3+ Tregs can be induced in vitro from CD4+CD25- T cells using TGF-b (54-55), and adoptively transferred polyclonal CD4+CD25-Foxp3- T cells can differentiate into CD4+CD25+Foxp3+ T cells in recipient mice following homeostatic proliferation (56).
Additionally, CD4+ cells can become IL-10-producing Tr1 cells when repeatedly stimulated with IL-10 or with immature DC (23), vitamin D3 and dexamethasone (57). Adaptive Tregs may have similar phenotype and function as natural Tregs since both types of lymphocytes can suppress immunological responses, yet they may differ in the mechanisms of action because natural Tregs can require direct cell-cell interaction for suppression (as shown in transwell experiments where supernatants from activated Tregs do not display suppressive properties) (49), whereas soluble factors (e.g. TGF-b) may be necessary for optimal action and maintenance of adaptive Tregs (54).
4. PHENOTYPE OF TREGS
Since CD25 - the a receptor for IL-2 - may not be unique to Tregs but is also expressed by conventional activated CD4+ T cells, additional surface marker have been searched for reliable identification of suppressor Tregs. Recently, the a chain of the IL-7 receptor (CD127) has been proposed for a rapid phenotypic identification of the Tregs. This marker is present at low levels on the surface of Tregs (CD127low) and at high levels on activated effector T cells (CD127high) (58-59).
Other molecules that contribute to the phenotype of the CD4+CD25+ Tregs and that cannot yet be considered unique markers because of some overlap of expression with effector CD4 T cells include the glucocorticoid-induced tumor necrosis factor receptor (GITR), the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4 or CD152 - high intracellularly, low on cell surface), CD62Lhigh, CD45RBlow, CD103 (integrin aEb7), neuropilin-1, membrane-bound TGF-b (in form of latency-associated protein, LAP), CD5, CD27, CD38, CD39, CD69, CD73, CD122, OX-40 (CD134), CCR4, CCR7, CCR8, TNF-R2, LAG-3 and, last but not least, the intracellular forkhead/winged helix transcription factor Foxp3 (60-63), which is currently considered the most reliable marker to monitor functional Tregs (64).
The important role of Foxp3 in the activity of Tregs and in autoimmunity is best exemplified by the observation that genetic deficiency of Foxp3+ cells in scurfy mice (17) or in humans affected by the IPEX syndrome (an X-linked syndrome characterized by immune dysregulation, polyendocrinopathy, enteropathy) (65) causes lymphoproliferative, rapidly lethal autoimmune disease.
5. MECHANISMS OF ACTION OF TREGS
Tregs may not require antigen specificity in their mechanisms of suppression, although the activation of these cells seems to occur preferentially via the engagement of the T-cell receptors (TCR) on these cells (69). Like conventional T cells, Tregs are selected with different affinity/avidity for the TCR and are enriched in self-reactive cells, as suggested by adoptive transfer studies (66-70). Overall, Tregs can be activated by self-antigens and non-self-antigens and may use or not antigen specificity for suppression in vitro and in vivo (71-75, 26).
Regarding IL-2, many studies have shown that this cytokine is important for the development, peripheral survival, and suppressive function of Tregs through events that may not be linked to a modulated expression of Foxp3 (76). IL-2 produced at sites of inflammation could contribute to drive Treg suppression (77), and peripheral survival and expansion of Tregs could depend on the presence of IL-2 (78).
Notably, mice deficient in IL-2, IL-2R, or IL-2Rb have reduced numbers of natural Tregs and die from a lymphoproliferative autoimmune syndrome (79) despite the fact that IL-2-/- and IL-2R-/- Tregs are functional and can suppress T-cell proliferation in vitro (80). These observations suggest that IL-2 can be required to sustain in vivo the homeostasis of natural Tregs (78) - possibly together with other signals for peripheral T cell survival including the encounter with MHC/self peptides (81), cytokines, and co-stimulatory molecules (82-84). Moreover, it has been shown that thymic generation of Tregs requires an intact IL-2/IL-2R pathway (85-86), yet the presence of a thymus is not an absolute requirement for the generation of Tregs and these cells can be generated in the periphery and/or from CD4+CD25- T cells (87-88).
5.1. In vitro suppression
Activated Tregs suppress target cells in a cell-contact-dependent, cytokine-independent mechanism (89). CD80 and CD86 ligands on T cells might bind to CTLA-4 on the Tregs during suppression, and this might be a reason why cell contact is necessary. Other molecules influencing the susceptibility of target cells to suppression by Tregs include GITR and GITR-ligand (GITR-L) (90) and, possibly, cell surface-bound TGF-b (91).
Regarding the target cell, after the encounter with the Tregs the effector T cells can display an arrest in cell cycle progression caused by uncoupled IL-2 signaling (92). Moreover, the activation of Tregs by anti-CD3 and anti-CD46 results in the expression of granzyme A, which facilitates the killing of the targets by a perforin-dependent Fas-Fas ligand-independent mechanism (46, 43). A granzyme B-dependent perforin-independent mechanism has also been identified for the suppressive activity of the Tregs (93).
The specific mechanisms of action of Foxp3, GITR, and CTLA-4 in Treg suppression are currently under intense investigation. It is clear that abrogation of the activity of any of these molecules reduces significantly the suppressive capacity of the Tregs. For example, antibody-mediated inhibition of CTLA-4 can abrogate the protective effects of Tregs in murine inflammatory bowel disease (94), possibly because CTLA-4 on Tregs could transduce a costimulatory activating signal along with TCR signaling (95).
It has also to be considered that there are molecules that can counteract the suppressive activity of the Tregs. For example, ligation of Toll-like receptor-2, -4, -8 and -9 results in the abrogation of Treg-mediated suppression (see below). Toll-like receptors (TLR) are molecules that recognize pathogen-associated molecular patterns (PAMP) common to different pathogens. Upon activation, TLR can stimulate adaptive immune responses through the activation of DC and the upregulation of costimulatory molecules and inflammatory cytokines including IL-6, TNF-a and IL-12 (96). The engagement of TLR-4 or TLR-9 on murine splenic DC can abrogate the suppressive activity of Tregs in vitro - possibly via the induction of a resistance of target cells to Treg-mediated suppression (a phenomenon that is dependent in part on DC-derived IL-6) (97). Also, TLR-9 deficiency in MRL mice leads to exacerbated lupus apparently as a result of increased T-cell activation associated with impaired Treg suppressive capacity in vitro (98-99).
5.2. In vivo suppression
The in vitro hyporesponsiveness to antigenic stimulation of the Tregs can be overcome by stimulation with anti-CD3 antibody and IL-2. Although Tregs are anergic in vitro, they do proliferate in vivo in response to antigen (100-101, 68). Available data suggest that the suppression in vitro of the Tregs may not reflect their in vivo activity, and additional factors such as Tregs migration and homing might influence significantly the activity of these cells, particularly at sites of inflammation (75). In particular, the differential expression of CD62L and CD27 on human CD4+CD25high Tregs could distinguish Treg subsets with migratory properties, i.e. CD27-CD62L- Tregs could be destined to periphery, CD62L+CD27+ Tregs would home to lymph nodes (102-106), and Tregs expressing CCR6 and CD45RO would accumulate in tissue (105). Ultimately, the accumulation of Tregs in tissue could limit the activity of effector target cells and subsequent inflammation at sites of organ damage. These considerations could contribute to explain why soluble factors may not be involved in the in vitro suppression mediated by the Tregs whereas in vivo the Tregs may need IL-10 and TGF-b to suppress target cells (106-107), and/or why Tregs can inhibit target cell transcription of IL-2 in vitro (108) while in vivo they may suppress independently on IL-2 involvement (80).
6. NATURAL TREGS AND AUTOIMMUNITY
The dysregulation of immune tolerance has a central role in the development and progression of pathogenic autoimmunity, and mice with an autoimmune background typically have reduced numbers of CD4+CD25+ T cells when compared to non-autoimmune mice. We summarize below the role of Tregs in the pathogenesis of several organ specific and systemic autoimmune diseases.
6.1. Natural Tregs and organ-specific autoimmunity
6.1.1. Multiple sclerosis
Experimental autoimmune encephalomyelitis (EAE) is a disease model for human multiple sclerosis (MS), and is mediated by encephalitogenic CD4+ T cells. Mice that harbor myelin basic protein (MBP)-specific CD4+ T cells have high incidence of disease due to the failure of Tregs to control pathogenic T cells (109). Tregs can inhibit in vitro the proliferation and cytokine production by myelin oligodendrocyte glycoprotein (MOG)-specific Th1 cells and can confer in vivo protection against EAE (33).
In humans, a functional dysfunction and a reduced number of Tregs has been described in patients with MS (110-111).
6.1.2. Type-1 diabetes
The progression of benign to aggressive insulitis in type-1 diabetes-prone female nonobese diabetic (NOD) mice is associated with a peripheral deficit of Tregs in pancreatic lymph nodes and pancreatic islets (112-115). In NOD mice, the functional potency and intra-pancreatic proliferative potential of natural Tregs declines with age, augmenting in turn the diabetogenic responses and the development of the disease (116). Notably, the adoptive transfer of Treg-depleted splenocytes in rodents exacerbates disease (113), whereas the transfer of either Tregs from diabetes-resistant animals (117) or Tregs expanded in vitro suppresses the disease (118). Since Tregs isolated from pancreatic lymph nodes - but not from peripheral lymph nodes - delay the progression of diabetes (119), it has been proposed to use antigen-specific Tregs for the prevention and/or reversal of experimental diabetes, with encouraging preliminary results (120).
In humans, the role of Tregs in type-1 diabetes is suggested by the finding of a functional deficit and impaired suppressive capacity of these cells (121). Importantly, rapamycin can allow the growth of functional Tregs while contributing to the depletion of effector T cells, envisioning a rapamycin-based, Treg-targeted immunotherapy in the disease (122).
6.1.3. Inflammatory bowel disease
The development of experimental colitis induced by the transfer of naïve CD4+CD45RBhigh T cells into syngeneic immuno-deficient mice (123) is prevented by co-transfer of regulatory CD4+CD45RBlow T-cells (124). In a murine model for human inflammatory bowel disease (IBD), CD4+CD25+Foxp3+ Tregs suppress effector T cell responses through mechanisms of cytokine deprivation-induced apoptosis (125), and their suppressive activity can be shown at the site of organ damage - the intestinal lamina propria (126).
In humans, the number of peripheral Tregs in IBD patients correlates with changes in disease activity, as it increases during remission and decreases with active disease (127).
6.1.4. Experimental autoimmune thyroiditis
Several studies suggest that Tregs might effectively modulate experimental autoimmune thyroiditis, a mouse model for Hashimoto's thyroiditis (128-130). This is relevant because patients with autoimmune thyroiditis may suffer from a reduced suppressive capacity of the Tregs.
6.2. Natural Tregs and systemic autoimmunity
6.2.1. Systemic lupus erythematosus
Studies in murine models of SLE have suggested that a deficit of Tregs can contribute to loss of self-tolerance and subsequent development of clinical manifestations of the disease (131). Additionally, adoptive transfer of ex vivo expanded Tregs can slow the progression of renal disease and decrease the mortality in transferred mice (39).
In view of the finding that some lupus-prone mice also have a reduced sensitivity of CD4+CD25- effector T cells to the suppression by Tregs (132), it can be hypothesized that the dysfunction of immune homeostasis in murine lupus might be partly associated with an abnormal number/function of Tregs and/or a reduced resistance of the target cells to Treg suppression, depending on the animal model considered.
In human SLE, the number of natural Tregs is decreased during active disease flares (133-134) and in active SLE pediatric patients (135). Interestingly, those defects can be reversed in vitro by Treg activation - a process which renders the defective SLE Tregs functional suppressor cells (136).
6.2.2. Autoimmune rheumatic diseases
Depletion of Tregs accelerates collagen-induced arthritis in mice (137), whereas adoptive transfer of Tregs protects mice from the systemic, chronic joint inflammation (138).
In humans, early rheumatoid arthritis (RA) associates with a reduced number of peripheral Tregs (139), although functional Tregs can be found enriched in the synovial fluid of patients with RA (140). It is possible that these cells may not be fully functional also because they have a decreased in vitro capacity to suppress the production of IFN-g and TNF-a in target CD4+CD25− T cells (141).
Of note, patients with relatively benign oligoarticular juvenile idiopathic arthritis have higher frequency of Tregs than patients with oligoarticular juvenile arthritis, a disease with a less favorable prognosis (142).
7. CONCLUSION
Although Tregs have the potential to reestablish immune tolerance to self-antigens both in new-onset and established disease in several experimental settings, they carry at the meantime the potential for detrimental effects due to the suppression of effector immune responses to tumors and microorganisms. Therapeutic considerations for targeting Tregs in autoimmunity remain nonetheless an appealing possibility, particularly because of the encouraging data obtained in animal models. Future studies of Treg-based immunotherapy will need to focus on how to circumvent the current obstacles, i.e. to define more specific markers for these cells, to keep in mind the differences between human and rodent Tregs, and to consider their site of action and the interactions with other immune cells and cytokine milieu where they operate.
8. ACKNOWLEDGMENTS
A.L.C. is supported by the National Institutes of Health grants AR53239 and AI63515.
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Key Words: Regulatory T cells (Tregs), Immune tolerance, Autoimmunity, Review
Send correspondence to: Antonio La Cava, Department of Medicine at the University of California Los Angeles, 1000 Veteran Avenue 32-59, Los Angeles, California 90095-1670. Tel: 310-267-4975, Fax: 310-206-8606, E-mail:alacava@mednet.ucla.edu