Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance ...and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies. However, in contrast to congenital deficiency, this was not fatal. CTLA-4 deletion induced preferential expansion of CD4⁺Foxp3⁺ Treg cells. However, T cells from CTLA-4–deficient inducible KO mice were able to adoptively transfer the diseases into T cell-deficient mice. Notably, cell transfer of thymocytes de novo produced myocarditis, otherwise not observed in donor mice depleted in adulthood. Moreover, CTLA-4 deletion in adult mice had opposing impacts on induced autoimmune models. Thus, although CTLA-4–deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of protein-induced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression.
Regulatory T cells (Tregs), either natural or induced, suppress a variety of physiological and pathological immune responses. One of the key issues for understanding Treg function is to determine how ...they suppress other lymphocytes at the molecular level in vivo and in vitro. Here we propose that there may be a key suppressive mechanism that is shared by every forkhead box p3 (Foxp3)+ Treg in vivo and in vitro in mice and humans. When this central mechanism is abrogated, it causes a breach in self-tolerance and immune homeostasis. Other suppressive mechanisms may synergistically operate with this common mechanism depending on the environment and the type of an immune response. Further, Treg-mediated suppression is a multi-step process and impairment or augmentation of each step can alter the ultimate effectiveness of Treg-mediated suppression. These findings will help to design effective ways for controlling immune responses by targeting Treg suppressive functions.
It is controversial how cytotoxic T lymphocyte antigen (CTLA)-4, a co-inhibitory molecule, contributes to immunological tolerance and negative control of immune responses. Its role as an inducer of ...cell-intrinsic negative signals to activated effector T cells is well documented. However, there is accumulating evidence that CTLA-4 is essential for the function of naturally occurring Foxp3+ regulatory T (Treg) cells, which constitutively express the molecule. CTLA-4 deficiency in Foxp3+ Treg cells indeed impairs their in vivo and in vitro suppressive function. Further, Treg cells can modulate the function of CD80- and CD86-expressing antigen-presenting cells via CTLA-4. Here we discuss how CTLA-4 expression by one T cell can influence the activation of another in a cell non-autonomous fashion and thus control immune responses.
Summary
The current review on the function of neutrophil cytosolic factor 1 (NCF1) and induced reactive oxygen species (ROS) is based on a genetic search for the major genes controlling autoimmune ...inflammatory disorders. Surprisingly, the disease‐promoting allele determined a lower ROS response and was therefore in complete contrast to the prevailing dogma. Once cloned, it opened the possibility to dissect this complex field from a new angle and with the possibilities to study the role of ROS in vivo. We found that NCF1 and NADPH oxidase 2 (NOX2) complex‐derived ROS is an important regulator of several chronic inflammatory disorders by using models for rheumatoid arthritis, multiple sclerosis, psoriasis and psoriasis arthritis, gout, and lupus. ROS could therefore affect many different types of diseases and the common denominator seems to be that ROS regulate macrophages, which prevents inflammation from going chronic. The role of ROS is currently changing from being seen as toxic agents that will promote inflammation toward a more complex view with ROS as crucial regulators of immune and inflammatory pathways.
Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan ...from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by γδ T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcγ receptor III, mast cells, and histamine) and adaptive immune players (αβ T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-α secretion and stimulation of local γδ T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
Peripheral self‐tolerance and immune homeostasis are maintained, at least in part, by the balance between Treg and effector T cells. Naturally, arising CD25+CD4+ Treg, which express the transcription ...factor Foxp3, suppress the activation and proliferation of other lymphocytes in multiple ways. A CTLA‐4‐dependent suppressive mechanism is shared by every Foxp3+ Treg at any location and its disruption breaches self‐tolerance and immune homeostasis, suggesting that it is a core mechanism of suppression. Depending on the environment, Foxp3+ Treg also differentiate to exhibit additional suppressive mechanisms, including the secretion of immunosuppressive cytokines. Naïve T cells acquire Foxp3 expression and suppressive activity under certain in vivo and in vitro conditions, whereas some Foxp3+ T cells may lose Foxp3 and suppressive activity following proliferation in an IL‐2‐deficient environment. Moreover, activated effector T cells frequently secrete suppressive cytokines, such as IL‐10, in a negative feedback fashion. These findings, when taken together, indicate that peripheral immune tolerance and homeostasis are dynamically maintained by functional differentiation within the Foxp3+ population, occasional conversion between Treg and non‐Treg cells, and the interactions among them. These dynamics provide ample opportunities for immune intervention for the benefit of the host.
CD25+CD4+ Regulatory T cells (Treg) represent a unique population of lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data have now confirmed the essential ...role played by these cells in a host of clinically relevant areas such as self-tolerance, transplantation, allergy and tumor/microbial immunity. Despite this mass of knowledge, significant gaps in our understanding of fundamental Treg biology remain, particularly regarding their development and mechanisms of suppression. In this review we attempt to highlight the current controversies and directions in which this exciting field is moving.
Thymus-produced CD4 ⁺ regulatory T (Treg) cells, which specifically express the transcription factor forkhead box p3, are potently immunosuppressive and characteristically possess a self-reactive ...T-cell receptor (TCR) repertoire. To determine the molecular basis of Treg suppressive activity and their self-skewed TCR repertoire formation, we attempted to reconstruct these Treg-specific properties in conventional T (Tconv) cells by genetic manipulation. We show that Tconv cells rendered IL-2 deficient and constitutively expressing transgenic cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) were potently suppressive in vitro when they were preactivated by antigenic stimulation. They also suppressed in vivo inflammatory bowel disease and systemic autoimmunity/inflammation produced by Treg deficiency. In addition, in the thymus, transgenic CTLA-4 expression in developing Tconv cells skewed their TCR repertoire toward higher self-reactivity, whereas CTLA-4 deficiency specifically in developing thymic Treg cells cancelled their physiological TCR self-skewing. The extracellular portion of CTLA-4 was sufficient for the suppression and repertoire shifting. It interfered with CD28 signaling to responder Tconv cells via outcompeting CD28 for binding to CD80 and CD86,or modulating CD80/CD86 expression on antigen-presenting cells. Thus, a triad of IL-2 repression, CTLA-4 expression, and antigenic stimulation is a minimalistic requirement for conferring Treg-like suppressive activity on Tconv cells, in accordance with the function of forkhead box p3 to strongly repress IL-2 and maintain CTLA-4 expression in natural Treg cells. Moreover, CTLA-4 expression is a key element for the formation of a self-reactive TCR repertoire in natural Treg cells. These findings can be exploited to control immune responses by targeting IL-2 and CTLA-4 in Treg and Tconv cells.
Forkhead box protein 3–positive regulatory T (Treg) cells are indispensable for the maintenance of self-tolerance and immune homeostasis. They can also be exploited for the treatment of immunologic ...diseases, including autoimmune diseases and allergy, by way of activating and expanding antigen-specific Treg cells in vivo . Cell therapy with in vitro activated and expanded Treg cells can be another therapeutic modality. The feasibility of such Treg cell–based therapeutic strategies is discussed based on recent advances in our understanding of the molecular and cellular basis of Treg cell development and function.
Immunological self tolerance is maintained at least in part by regulatory T (T(reg)) cells that actively and dominantly control potentially hazardous self-reactive T cells in the periphery. Antigens ...that stimulate self-reactive T cells may also activate natural T(reg) cells, thereby maintaining dominant self tolerance. Conversely, genetic anomalies or environmental agents that specifically or predominantly affect T(reg) cells cause or predispose to autoimmunity. With recent advances in our understanding of T(reg) cell development in the thymus and periphery and the molecular mechanism of T(reg) cell-mediated suppression, new ways of treating immunological diseases by targeting T(reg) cells at the cellular and molecular levels are envisaged.
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