ReviewThe role of different subsets of T regulatory cells in controlling autoimmunity
Introduction
Immunological tolerance is a feature of the immune system that is intimately related to discrimination between self and non-self. Recent data suggest that T regulatory cells (Tr cells)—in addition to clonal deletion and anergy—play a critical role in the generation and maintenance of tolerance. However, a great deal of uncertainty remains about the lineages, differentiation factors, antigen specificity and mechanisms of action of Tr cells. It will not be a straightforward task to clarify these points as several types of Tr cells exist and each type may have a unique mechanism of action, which may vary depending on the experimental model. Furthermore, attempts to characterise Tr cells have been hampered by the fact that, in general, they have low proliferative capacity in vitro. Despite these limitations, much progress has been made since the last review on Tr cells and immune pathology in this journal [1]. The role of Tr cells in transplantation has been recently reviewed [2]. Herein we focus on the role of Tr cells, and in particular on CD4+ Tr cells, in prevention of autoimmunity and maintenance of homeostasis. The reader is also referred to other recent reviews on Tr cells [3], [4.
Section snippets
The relationship between anergy, suppression and Tr cells
T cell anergy may be defined as a failure to proliferate and produce IL-2 upon antigen stimulation. In contrast, suppression is an active process, usually mediated by regulatory cells that can be adoptively transferred. Although not yet clearly understood, there is growing evidence that anergy and suppression are not distinct but, rather, are linked mechanisms, possibly involving the same cells in different stages of their differentiation. These mechanisms ultimately mediate peripheral
The role of co-stimulatory molecules and cytokines in the differentiation of CD4+ Tr cells
The precise signals that promote the generation of Tr cells remain to be determined but considerable evidence suggests that co-stimulatory molecules and cytokines play an important role. For example, generation of CD4+CD25+ Tr cells was CD28-dependent [11]. In addition, in murine experimental autoimmune encephalomyelitis (EAE), B7.2 (CD86) was required for the generation of oral tolerance with low doses of antigen (which is generally associated with induction of Tr cells) [12]. Similarly,
The effector function of CD4+CD45RBlow, Th3 and Tr1 cells
Tr cells within the CD4+CD45RBlow T cell subset, Th3 and Tr1 cells can be distinguished from other CD4+ Tr cells because, unlike other Tr cells, they clearly exert their regulatory effects via production of the immunosuppressive cytokines TGF-β and/or IL-10. Both TGF-β and IL-10 have immunosuppressive effects on APCs and T cells. Therefore these cytokines may render the APCs tolerogenic and at the same time directly suppress naive T cells. The action of TGF-β on T cells is critical for
Murine Tr cells that produce suppressive cytokines
Inflammatory bowel disease (IBD) can be induced in immunodeficient mice by transfer of CD4+CD45RBhi (i.e. naive) T cells. Importantly, co-transfer of CD4+CD45RBlow cells protected these mice from disease via a TGF-β-dependent mechanism, demonstrating that Tr cells reside within the CD4+CD45RBlow subset [1]. Although initial studies performed with neutralizing anti-IL-10 monoclonal antibodies (mAbs) indicated that IL-10 was dispensable for the suppressive effects of CD4+CD45RBlow cells, later
Human Tr cells that produce suppressive cytokines
The majority of studies that identified a role for Tr cells in peripheral tolerance were performed in murine models. However, there are several key reports indicating that Tr cells also exist in the human. Following cloning of human CD4+ T cells activated with alloantigens in the presence of IL-10, Tr1 cells were isolated [10]. These cells are distinct from classical Th1 or Th2 cells in their cytokine production: high levels of IL-10; normal levels of TGF-β; moderate amounts of IFN-γ and IL-5;
Is there a role for IL-4 in regulation by CD4+ Tr cells?
There are several studies that suggest a role for IL-4 in regulation of autoimmunity by Tr cells. In a virus-induced model of autoimmune diabetes, protection by Tr cells induced by oral insulin feeding was abrogated in mice genetically deficient for IL-4 or STAT-6 [42]. Seddon and Mason [43] have shown that prevention of autoimmune thyroiditis in thymectomized and irradiated rats, by either CD4+CD45RC– peripheral cells or CD4+ thymocytes, could be blocked by either neutralizing anti-TGF-β or
CD4+CD25+ Tr cells
Another CD4+ Tr cell subset has been defined, based on constitutive expression of IL-2Rα (i.e. the α chain of the IL-2-receptor; it is also known as CD25) [3]. CD4+CD25+ T cells comprise 5–10% of peripheral T cells in normal mice and exhibit potent immunoregulatory functions in vitro and in vivo. Whether a similar population of CD4+CD25+ Tr cells exists in the human has not yet been defined. Transfer of CD4+CD25+ T cells suppressed induction of autoimmune disease by autoreactive T cells in
Other types of CD4+ Tr cells
CD4+ Tr cells that neither suppress via a IL-10/TGF-β-dependent mechanism nor express CD25 constitutively have been described. Mice transgenic for a TCR that is directed against the self-antigen MBP were crossed with mice deficient in recombinase activation genes; the F1 generation developed spontaneous autoimmune encephalomyelitis due to the lack of CD4+ Tr cells [54], [55]. The relationship of these CD4+ Tr cells with those described above remains to be determined as they were not contained
Additional subsets of Tr cells
CD8+ Tr cells have been described in a number of experimental autoimmune disease models and it has been proposed that, in addition to CD4+ cells, CD8+ Tr cells may also have a role in oral tolerance since suppression can be adoptively transferred by both subsets [23], [60], [61]. However, there is evidence that CD8+ Tr cells that are induced by oral tolerance are only required for local intestinal suppression [62] and not for systemic hyporesponsiveness [23], [63]. Furthermore, it cannot be
Conclusions
At present, the population of cells that is designated as Tr cells consists of several subsets that have been characterized in various experimental models, using different assays. Therefore, the relationship between the subsets is currently difficult to understand. A better knowledge of the ontogeny/induction and effector functions of these cells will help us to reconcile discrepancies between different studies, to determine how many distinct subsets of Tr cells truly exist, to define whether
Acknowledgements
We thank Bruce Blazar, Paul Orban and Loı̈c Dupré for critical reading of the manuscript and Luisella Meroni for excellent secretarial assistance. MKL is a post-doctoral fellow of the Canadian Institutes for Health Research. Our work is supported by a grant from the Italian Telethon Foundation.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
of special interest
of outstanding interest
References (81)
- et al.
Control of immune pathology by regulatory T cells
Curr Opin Immunol
(1998) - et al.
What is the role of regulatory T cells in transplantation tolerance?
Curr Opin Immunol
(1999) Regulatory T cells: key controllers of immunologic self-tolerance
Cell
(2000)- et al.
B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes
Immunity
(2000) - et al.
Abrogation of TGF beta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease
Immunity
(2000) - et al.
Regulatory T cells and inflammatory bowel disease
Immunol Today
(1999) - et al.
Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway
Immunity
(1999) - et al.
Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice
Gastroenterology
(2000) Regulatory T cells in autoimmmunity
Annu Rev Immunol
(2000)- et al.
Anergic T cells act as suppressor cells in vitro and in vivo
Eur J Immunol
(1999)