Peripheral generation and function of CD4+CD25+ regulatory T cells

Infection and Immunity Research Group, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, UK.
Current topics in microbiology and immunology (Impact Factor: 4.1). 02/2005; 293:115-31. DOI: 10.1007/3-540-27702-1_6
Source: PubMed


The balance between immunity and tolerance is important to maintain immune homeostasis. Several mechanisms are in place to ensure that the immune response is controlled, such as T cell anergy, apoptosis and immune ignorance. A fourth mechanism of peripheral tolerance is the active suppression by regulatory or suppressor T cells. The existence of suppressor T cells was first described in the early 1970s, but these cells became discredited in the 1980s. The work of Shimon Sakaguchi and others, however, has brought these cells back into the limelight and nowadays research into regulatory/suppressor T cells is a very active field of immunology. Different types of regulatory T cells have been described, including CD4+CD25+ T cells that constitutively express CTLA-4, GITR and Foxp3, TGF-beta producing Th3 cells, IL-10 producing Tr1 cells, and CD8+CD28- T cells. This review will focus on the generation and function of CD4+CD25+ regulatory T cells. CD4+CD25+ regulatory cells were originally described as thymus-derived anergic/suppressive T cells. Recent papers, however, indicate that these cells might also be generated in the periphery. CD4+CD25+ regulatory T cells can be activated by self-antigens and non-self-antigens, and once activated can suppress T cells in an antigen nonspecific manner. Interestingly, the suppressive effects of these cells are not restricted to the adaptive immune system (T and B cells) but can also affect the activation and function of innate immune cells (monocytes, macrophages, dendritic cells). These features make the CD4+CD25+ regulatory T cell subset an interesting target for immunotherapy of chronic inflammatory or autoimmune diseases.

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    • "This provides independent evidence that even small increases in Treg populations can have a significant effect on the amelioration of inflammatory disease. Although Tregs were initially thought to originate exclusively in the thymus [32], subsequent studies in mice and humans showed that CD4+CD25hiFoxP3+ adaptive or induced Tregs can develop in the periphery under a variety of conditions [2, 33]. "
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    ABSTRACT: HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called "Tregitopes") have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4(+) T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells' (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.
    Journal of Diabetes Research 04/2013; 2013(3):621693. DOI:10.1155/2013/621693 · 2.16 Impact Factor
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    • "Peripheral Tregs can also be generated through interactions between IL-4 or IL-13 and the IL-4Rα [80]. Although, FOXP3 is a characteristic marker of nTregs, Th3 cells can also be induced to generate FOXP3 [81–83]. Upon activation of the T cell receptor, Tregs suppress dendritic cells, B cells, macrophages, osteoblasts, mast cells, NK cells, NKT cells, CD4+ T, and CD8+ T cells [84]. "
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    ABSTRACT: Heat shock proteins (HSPs) are important molecules required for ideal protein function. Extensive research on the functional properties of HSPs indicates that HSPs may be implicated in a wide range of physiological functions including immune function. In the immune system, HSPs are involved in cell proliferation, differentiation, cytokine release, and apoptosis. Therefore, the ability of the immune system, in particular immune cells, to function optimally and in unison with other physiological systems is in part dependent on signaling transduction processes, including bidirectional communication with HSPs. Regulatory T cells (Tregs) are important T cells with suppressive functions and impairments in their function have been associated with a number of autoimmune disorders. The purpose of this paper is to examine the relationship between HSPs and Tregs. The interrelationship between cells and proteins may be important in cellular functions necessary for cell survival and expansion during diseased state.
    03/2013; 2013:813256. DOI:10.1155/2013/813256
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    • "Although both NKT cells and Tregs could develop in response to self-antigens, their broad immunoregulatory function has been observed to operate in an antigen non-specific manner (Liu et al., 2006; Masteller et al., 2006). They have been shown to play a strong role in controlling inflammation and autoimmunity in the periphery (Taams and Akbar, 2005), including as antigen-specific Tregs generated in inflamed tissues such as in the central nervous system (Liu et al., 2006). "
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    ABSTRACT: Complex immune responses have evolved to protect multicellular organisms against the invasion of pathogens. This has exerted strong developmental pressure for specialized functions that can also limit damage to self-tissue. Two arms of immunity, the innate and adaptive immune systems, have evolved for quick, non-specific immune responses to pathogens and more efficient, long-lasting ones upon specific recognition of recurrent pathogens. Specialized cells have arisen as the sentinels of these functions, including macrophages, natural killer (NK), and T and B-lymphocytes. Interestingly, a population of immune cells that can exert both of these complex functions, NKT cells, not only share common functions but also exhibit shared cell surface markers of cells of both arms of the immune system. These features, in combination with sophisticated maintenance of immune homeostasis, will be discussed. The recent finding of self-peptide reactivity of NKT cells in the context of CD1d, with capacity to regulate multiple autoimmune and inflammatory conditions, motivates the current proposal that self-reactive NKT cells might be the ancestral link between present NK and T cells. Their parallel selection through evolution by higher vertebrates could be related to their central function as master regulators of immune homeostasis that in part is shared with regulatory T cells. Hypothetical views on how self-reactive NKT cells secure such a central role will also be proposed.
    Journal of Molecular Cell Biology 12/2011; 4(2):70-8. DOI:10.1093/jmcb/mjr035 · 6.77 Impact Factor
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