Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in regional lymph node

Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 10/2005; 202(6):771-81. DOI: 10.1084/jem.20041033
Source: PubMed


This study investigated the unresolved issue of antigen-dependency and antigen-specificity of autoimmune disease suppression by CD4+CD25+ T cells (T regs). Based on autoimmune ovarian disease (AOD) in day 3 thymectomized (d3tx) mice and polyclonal T regs expressing the Thy1.1 marker, we determined: (a) the location of recipient T cell suppression, (b) the distribution of AOD-suppressing T regs, and (c) the relative efficacy of male versus female T regs. Expansion of recipient CD4+ T cells, activation/memory marker expression, and IFN-gamma production were inhibited persistently in the ovary-draining LNs but not elsewhere. The cellular changes were reversed upon Thy1.1+ T reg depletion, with emergence of potent pathogenic T cells and severe AOD. Similar changes were detected in the regional LNs during autoimmune dacryoadenitis and autoimmune prostatitis suppression. Although the infused Thy1.1+ T regs proliferated and were disseminated in peripheral lymphoid organs, only those retrieved from ovary-draining LNs adoptively suppressed AOD at a suboptimal cell dose. By depriving d3tx recipients of ovarian antigens, we unmasked the supremacy of ovarian antigen-exposed female over male T regs in AOD suppression. Thus, disease suppression by polyclonal T regs depends on endogenous antigen stimulation; this occurs in a location where potent antigen-specific T regs accumulate and continuously negate pathogenic T cell response.


Available from: Kenneth S K Tung, Aug 12, 2015
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    • "CD4 + CD25 + Treg cells have a potential to avert differentiation of autoimmune effector T cells from the peripheral pool of memory cells and therefore prevent disease development [101]. Antigen-dependent polyclonal CD4 + CD25 + Treg cells, in the regional lymph nodes serve a function of continuously regulating autoimmune responses throughout the course of the dis- ease [102] . Mechanisms of Treg cell-mediated immunological tolerance in MS have been critically reevaluated [103]. "
    [Show abstract] [Hide abstract] ABSTRACT: Cytokines are pleiotropic soluble mediators of cellular functions. Cytokines are critical in immune pathogenesis of human diseases, including autoimmune CD4(+) T cell mediated chronic inflammatory, demyelinating and neurodegenerative diseases of the central nervous system (CNS), multiple sclerosis (MS). In MS and its experimental model, experimental autoimmune encephalomyelitis (EAE), chronic persistence and/or reoccurrence of inflammation in the CNS causes chronic progressive or relapsing disease, accompanied with demyelination and damage to axons and oligodendrocytes, which ultimately leads to paralysis and disability. As opposed to other cytokines, whose effects are not limited to the CD4(+) T cell subset, IL-16 exerts its biological properties by exclusive binding and signaling through CD4 receptor. IL-16 selectively regulates migration of all CD4 expressing T cells regardless of their activation state, which is of critical importance for immune modulation and potential therapy of MS. Other major biological properties of IL-16 essential for the function of CD4(+) T cells include regulation of: T cell activation, CD25 expression, MHC class II expression, dendritic cell (DC)-T cell cooperation, B cell-T cell and T cell-T cell cooperation, inflammatory cytokine production and modulation of chemokine regulated T cell chemo-attraction. In this article we outline immune pathogenesis of the disease necessary to understand significance of cytokines and IL-16 in MS regulation. We revisit cytokine regulation with emphasis on involvement of IL-16 mechanisms, implicated in MS progression and important for development of new therapies. We emphasize the significance of similar IL-16 mechanisms for other chronic inflammatory CNS diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Feb 2015 · Cytokine
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    • "Although the limited understanding of Treg cell specificity has precluded a comprehensive test of this possibility in vivo, it is interesting to note that only Treg cells from male mice can effectively ameliorate autoimmune prostatitis caused by Treg cell depletion due to neonatal thymectomy (144). Conversely, autoimmune oophoritis is most effectively controlled by Treg cells from female mice, particularly those isolated from the tissue-draining lymph nodes (145). Thus, despite the fact that both male and female Treg cells presumably contain specificities for shared and ubiquitously expressed self-antigens present in the prostate and ovaries, these were not sufficient to prevent disease development, indicating a tremendous degree of antigen specificity in these regulatory responses. "
    [Show abstract] [Hide abstract] ABSTRACT: Foxp3(+) regulatory T cells (Treg cells) are essential for establishing and maintaining self-tolerance, and also inhibit immune responses to innocuous environmental antigens. Imbalances and dysfunction in Treg cells lead to a variety of immune-mediated diseases, as deficits in Treg cell function contribute to the development autoimmune disease and pathological tissue damage, whereas overabundance of Treg cells can promote chronic infection and tumorigenesis. Recent studies have highlighted the fact that Treg cells themselves are a diverse collection of phenotypically and functionally specialized populations, with distinct developmental origins, antigen-specificities, tissue-tropisms, and homeostatic requirements. The signals directing the differentiation of these populations, their specificities and the mechanisms by which they combine to promote organ-specific and systemic tolerance, and how they embody the emerging property of regulatory memory are the focus of this review.
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    • "These results suggest that in this experimental setting, the two different immune outcomes (graft protection or damage) are probably not caused by a difference in the numbers of T eff cells expanded during the priming phase. Alternatively, the results highlighted the critical requirement of sufficient recruitment of T reg cells to the inflammatory site and the continuous presence of T reg cells for optimal suppression , as suggested in previous studies with models of autoimmune oophoritis (Samy et al., 2005), islet transplantation (Zhang et al., 2009), and other models of immune-mediated (Tisch and Wang, 2008; Shevach, 2011). To further examine the behavior of T reg cells in a setting of severe imbalance with T eff cells, we examined the impact of acute removal of T reg cells after establishment of target tissue protection. "
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