Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance
Introduction
The development of autoimmune diseases like type 1 diabetes (T1D), involves a breakdown in the mechanisms that control self and non-self discrimination [1]. The primary mechanism that leads to tolerance to self-antigens is thymic clonal deletion of self-reactive T cells [2]. However, some self-reactive T cells may escape this process, recognize peripheral tissue antigens, and subsequently provoke autoimmunity [3]. Autoreactive T cells are normally present in all individuals, but autoimmune diseases affect only about 5% of the population suggesting that mechanisms for peripheral self-tolerance must exist to completely control potentially pathogenic T cells. Thus, a key feature of autoimmune diseases like T1D is a failure in immunoregulation and evidence has accumulated for an active mechanism of immune suppression in which regulatory T cells (Treg) suppress the activation and function of self-reactive T cells that escape other mechanisms of tolerance induction [2], [3], [4], [5].
The concept of regulatory or “suppressor” T cells emerged when it was shown that stimulation of the immune system by thymus-dependent antigens could give rise to the production of suppressor T cells that downregulate the differentiation of antigen-specific, effector T helper (Th) cells [3], [7]. A large number of studies were carried out with the aim of characterizing the phenotype of suppressor T cells and their mode of action, however, highly variable and inconsistent observations made it difficult to delineate the stable phenotypes or the molecular identity of the suppressor mechanism. For many years, it was uncertain whether specialized populations T cells mediated this regulatory function or whether this function represented one of many of non-specialized T cells. In recent years, however, a plethora of evidence indicates that T cell-mediated suppression indeed has a critical role in modulating immune responses to self and non-self antigens [1], [2], [3], [4], [5], [6], [7].
Section snippets
Multiple levels of T cell immunoregulation
In an attempt to refine and diversify its ability to control adaptive immune responses, the immune system has evolved numerous mechanisms, including Treg cells, to modulate and down-regulate immune responses at various times, locations and in various inflammatory circumstances. To this end, a network of Treg exists to assure timely and efficient T cell immunoregulation at multiple levels depending on the inflammatory status, co-stimulatory load, and anatomical location. Indeed, Treg cells come
Naturally occurring CD4+CD25+ regulatory T cells
Numerous attempts have been made to identify and characterize the phenotypic nature of this nTreg cell population present in the normal T cell repertoire. In fact, several markers have been shown to segregate with suppressive function, including CD45RBlow, CD38, CD62Lhi, DX5, and CD103 [16], [17], [18], [19], [20]. Most recent studies indicate that CD25 (IL-2 receptor (R) alpha (α) chain) appears to be the most specific, cell surface marker for the nTreg. CD4+CD25+ nTreg are the only CD4+ T
Role of cytokines in the mechanism underlying nTreg cell mediated protection
The relative contribution and regulation of nTreg-derived cytokines in tolerance induction and disease regulation remains controversial, and may depend on a number of context-dependent physiological factors including the nature of the target organ and magnitude of the antigenic/costimulatory burden. The relative contribution of potently immunosuppressive molecules such as IL-10 and transforming growth factor β1 (TGF-β1) in the suppressor function of nTreg has been vigorously debated in recent
Conclusions and future perspectives
One critical question that remains to be addressed is whether the onset of autoimmune disease results from a decline in Treg cell frequency and function, or from the overriding of such regulation by an uncontrollable activation and expansion of autoreactive T cells. The possibility remains that a selective decrease in frequency or function of nTreg cells in several autoimmune diseases may contribute to disease establishment, consistent with the notion that genetic susceptibility to autoimmune
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