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.

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Available from: Kenneth S K Tung, Aug 12, 2015
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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. "
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    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.
    Frontiers in Immunology 07/2014; 5:333. DOI:10.3389/fimmu.2014.00333
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    • "Furthermore, it has been shown that peripheral shaping of TCR repertoire plays an important role in Treg function [15] [16] [17] [18]. "
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    ABSTRACT: Regulatory T cells (Treg) are important for maintaining immune homeostasis. Adoptive transfer of Tregs is protective in renal disease models in both immunocompetent and immunodeficient mice. However the involvement of TCR recognition of renal antigens remains to be clarified. To address this question, we made use of Tregs from the DO11.10 mouse (a TCR transgenic (Tg) mouse), that recognise the non-murine antigen Ovalbumin (OVA) and therefore are not activated by renal antigens. DO11.10 Tregs were assessed functionally in vitro and demonstrated equivalent suppression to WT BALB/c Tregs. Adriamycin Nephropathy (AN) was induced in mice which had been transfused with CD4(+)CD25(+)Tregs isolated from DO11.10 or BALB/c mice. To eliminate the memory/activation state as a cause of differences in activity, the protective capacity of DO11.10 Tregs pre-activated with OVA in vivo was assessed. Transfer of WT BALB/c Tregs significantly attenuated the development of AN with less glomerulosclerosis, tubular atrophy and macrophage infiltration as compared to AN mice without Treg transfer. However, mice receiving either naïve or pre-activated DO11.10 Tregs were not protected from AN. The lack of protection by DO11.10 Tregs was not due to failure to traffic to the affected kidney. These results suggest that antigen recognition in the kidney is important for Treg protection against injury.
    International journal of clinical and experimental pathology 01/2013; 7(1):38-47. · 1.89 Impact Factor
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    • "CD4 + CD25 + Tregs are critical for peripheral tolerance. Tregs may control immune privilege within organs by preventing autoimmunity induction in regions where antigenspecific Tregs continuously encounter tissue antigens (Samy et al., 2005). This mechanism controls tolerogenic versus autoimmune response to sperm in vasectomy (Wheeler et al., 2011). "
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    ABSTRACT: The testis presents a special immunological environment, considering its property of immune privilege that tolerates allo- and auto-antigens. Testicular immune privilege was once believed to be mainly based on the sequestration of antigens from the immune system by the blood-testis barrier in the seminiferous epithelium. Substantial evidence supports the view that the combination of physical structure, testicular cells, and cytokines controls immune responses in the testis to preserve the structural and functional integrity of testicular immune privilege. Both systemic immune tolerance and local immunosuppression help maintain the immune privilege status. Constitutive expression of anti-inflammatory factors in testicular cells is critical for local immunosuppression. However, the testis locally generates an efficient innate immune system against pathogens. Disruption of these mechanisms may lead to orchitis and impair fertility. This review article highlights the current understanding of structural, cellular, and molecular mechanisms underlying the unique immune environment of the testis, particularly its immune privilege status.
    Frontiers in Immunology 06/2012; 3:152. DOI:10.3389/fimmu.2012.00152
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