T regulatory cells and allergy

Anergy, tolerance and active suppression may not be independent events, but rather involve similar mechanisms and cell types in immune regulation. Induction of allergen-specific T(Reg) cells seems essential for maintaining a healthy immune response towards allergens. By utilizing multiple secreted cytokines and surface molecules, antigen-specific T(Reg) cells may re-direct an inappropriate immune response against allergens or auto-antigens.     

How regulatory T cells work

Regulatory T (T(Reg)) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that T(Reg) cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by T(Reg) cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for T(Reg)-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T(Reg)-cell function.     

Optimal number of regulatory T cells

The adaptive immune system of a vertebrate may attack its own body, causing autoimmune diseases. Regulatory T cells suppress the activity of the autoreactive effector T cells, but they also interrupt normal immune reactions against foreign antigens. In this paper, we discuss the optimal number of regulatory T cells that should be produced. We make the assumptions that some self-reactive immature T cells may fail to interact with their target antigens during the limited training period and later become effector T cells causing autoimmunity, and that regulatory T cells exist that recognize self-antigens. When a regulatory T cell is stimulated by its target self-antigen on an antigen-presenting cell (APC), it stays there and suppresses the activation of other naive T cells on the same APC. Analysis of the benefit and the harm of having regulatory T cells suggests that the optimal number of regulatory T cells depends on the number of self-antigens, the severity of the autoimmunity, the abundance of pathogenic foreign antigens, and the spatial distribution of self-antigens in the body. For multiple types of self-antigen, we discuss the optimal number of regulatory T cells when the self-antigens are localized in different parts of the body and when they are co-localized. We also examine the separate regulation of the abundances of regulatory T cells for different self-antigens, comparing it with the situation in which they are constrained to be equal.     

Natural versus adaptive regulatory T cells

The regulation of immune responses to self-antigens is a complex process that involves maintaining self-tolerance while retaining the capacity to mount robust immune responses against invading microorganisms. Over the past few years, many new insights into this process have been gained, leading to the re-emergence of the idea that regulatory T (T(Reg)) cells are a central mechanism of immune regulation. These insights have raised fundamental questions concerning what constitutes a T(Reg) cell, where they develop and what signals maintain T(Reg)-cell populations in a functional state. Here, we propose the existence of two subsets of CD4+ T(Reg) cells--natural and adaptive--that differ in terms of their development, specificity, mechanism of action and dependence on T-cell receptor and co-stimulatory signalling.     

Manipulating dendritic cells to induce regulatory T cells

Dendritic cells (DCs) induce and regulate T-cell responses, and tolerogenic DCs can promote the development of regulatory T cells with suppressive activity. The possibility of manipulating DCs using different pharmacological or biological agents, enabling them to exert tolerogenic activities, could be exploited to better control a variety of chronic inflammatory conditions, from autoimmune diseases to allograft rejection.     

Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE

Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.     

Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis

Most cell surface markers for CD4⁺CD25⁺ regulatory T cells (Tregs) are also expressed by activated non-regulatory T cells. Recently, CD127 down-regulation was found to identify functional Tregs in healthy individuals, but there are no data from patients with inflammatory conditions. We examined peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis patients with active inflammation and from healthy controls, and found that CD4⁺ T cells contained an equal proportion of CD25⁺CD127⁻/low cells in both groups. In patients, not all these cells expressed intracellular FOXP3. Upon activation by anti-CD3/anti-CD28, PBMC rapidly down-regulated CD127, while FOXP3 up-regulation was transitory and occurred in fewer cells. The activated cells were not anergic to restimulation and had no suppressive effects. The distinct kinetics indicate that the FOXP3⁻CD127⁻/low cells in rheumatoid arthritis patients most likely represent activated non-regulatory T cells. This complicates the use of CD127 for identification of Tregs in inflammatory diseases.     

Differential suppression of tumor-specific CD8+ T cells by regulatory T cells

In the CT26 BALB/c murine model of colorectal carcinoma, depletion of regulatory T cells (Tregs) prior to tumor inoculation results in protective immunity to both CT26 and other BALB/c-derived tumors of diverse histological origin. In this paper, we show that cross-protection can be conferred by adoptively transferred CD8(+) CTLs. Other schedules for inducing immunity to CT26 have been described, but they do not lead to cross-protection. We show that Treg ablation facilitates the development of new CTL specificities that are normally cryptic, and have mapped the root epitope of one of these responses. This work has allowed us to demonstrate how the specificity of CTL responses to tumor Ags can be controlled via differential suppression of CTL specificities by Tregs, and how this can result in very different physiological outcomes.     

Thymus exosomes-like particles induce regulatory T cells

Exosomes released from different types of cells have been proposed to contribute to intercellular communication. We report that thymic exosome-like particles (ELPs) released from cells of the thymus can induce the development of Foxp3(+) regulatory T (Treg) cells in the lung and liver. Thymic ELPs also induce the conversion of thymic CD4(+)CD25(-) T cells into Tregs. Tregs induced by thymic ELPs suppress the proliferation of CD4(+)CD25(-) T cells in vitro and in vivo. We further show that neutralization of TGF-beta in ELPs partially reverses thymic ELP-mediated induction of CD4(+)Foxp3(+) T cells in the lung and liver. This study demonstrates that thymic ELPs participate in the induction of Foxp3(+) Tregs. Also, TGF-beta of thymic ELPs might be required for the generation of Tregs in the peripheral tissues.     

MicroRNA 10a marks regulatory T cells

MicroRNAs (miRNAs) are crucial for regulatory T cell (Treg) stability and function. We report that microRNA-10a (miR-10a) is expressed in Tregs but not in other T cells including individual thymocyte subsets. Expression profiling in inbred mouse strains demonstrated that non-obese diabetic (NOD) mice with a genetic susceptibility for autoimmune diabetes have lower Treg-specific miR-10a expression than C57BL/6J autoimmune resistant mice. Inhibition of miR-10a expression in vitro leads to reduced FoxP3 expression levels and miR-10a expression is lower in unstable "exFoxP3" T cells. Unstable in vitro TGF-?-induced, iTregs do not express miR-10a unless cultured in the presence of retinoic acid (RA) which has been associated with increased stability of iTreg, suggesting that miR-10a might play a role in stabilizing Treg. However, genetic ablation of miR-10a neither affected the number and phenotype of natural Treg nor the capacity of conventional T cells to induce FoxP3 in response to TGFβ, RA, or a combination of the two. Thus, miR-10a is selectively expressed in Treg but inhibition by antagomiRs or genetic ablation resulted in discordant effects on FoxP3.     

Utilizing regulatory T cells to control alloreactivity

Effective resetting of the immune system cannot be achieved by non-specific immunosuppression. Instead, novel strategies aim at harnessing the body's natural tolerance mechanisms to rectify an Ag-specific response without disturbing other immune functions. Fine-tuning of the balance between Ag-specific effector and regulatory T (Tr) cells is a promising strategy that requires detailed understanding of the differentiation and expansion pathways of the relevant Tr cell subsets. Here we review recent developments regarding the control of alloreactivity by induction and expansion of Tr cells. T-cell activation in the presence of tolerogenic APC and cytokines leads to the induction of Tr cells, which can mediate tolerance through cytokine-dependent and/or contact-dependent mechanisms. Better understanding of the mechanisms of immune regulation mediated by Tr cells may enable fine-tuning of specific immune responses and pave the way for novel therapeutic approaches.     

Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells

Regulatory T cells play a crucial role in the homeostasis of the immune response. In addition to CD4⁺Foxp3⁺ regulatory T cells, several subsets of Foxp3^- regulatory T cells, such as T helper 3 (Th3) cells and type 1 regulatory T (Tr1) cells, have been described in mice and human. Accumulating evidence shows that naïve B cells contribute to tolerance and are able to promote regulatory T cell differentiation. Naïve B cells can convert CD4⁺CD25^- T cells into CD25⁺Foxp3^- regulatory T cells, named Treg-of-B cells by our group. Treg-of-B cells express LAG3, ICOS, GITR, OX40, PD1, and CTLA4 and secrete IL-10. Intriguingly, B-T cell-cell contact but not IL-10 is essential for Treg-of-B cells induction. Moreover, Treg-of-B cells possess both IL-10-dependent and IL-10-independent inhibitory functions. Treg-of-B cells exert suppressive activities in antigen-specific and non-antigen-specific manners in vitro and in vivo. Here, we review the phenotype and function of Foxp3⁺ regulatory T cells, Th3 cells, Tr1 cells, and Treg-of-B cells.     

Signal transduction in T cells: an overview

The mitogenic in vitro activation of human peripheral blood lymphocytes is severely depressed in space as well as in models of low gravity conditions on ground. The mechanism of T-cell activation is very complex; 3 signals are required for full activation. A series of experiments performed in space and in modeled low gravity on ground have shown that a failure in the delivery of the second signal--interleukin-2--is one of the reasons for the impaired activation. The cytoskeleton plays a key role in several steps of the mitogenic activation; (1) in the binding of the mitogen to the cell membrane and the subsequent patching and capping of the receptors, and (2) in the transduction of the signals from the membrane to the nucleus. Changes in the cytoskeletal structures of vimentin and tubulin observed in cells exposed to low gravity conditions may have influenced the correct signal transduction.