Article

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

Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 10/2005; 202(6):771-81. DOI: 10.1084/jem.20041033
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
69 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune-mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models.Cellular & Molecular Immunology advance online publication, 20 October 2014; doi:10.1038/cmi.2014.97.
    Cellular & molecular immunology 10/2014; DOI:10.1038/cmi.2014.97 · 4.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ProblemThe phenotype and function of regulatory T (Treg) cells in rats with experimental autoimmune orchitis (EAO) was evaluated.Method of studyDistribution of Treg cells in draining lymph nodes from the testis (TLN) and from the site of immunization (ILN) was analysed by immunohistochemistry. The number, phenotype and proliferative response (5-bromo-2′-deoxyuridine incorporation) of Treg cells were evaluated by flow cytometry and Treg cell suppressive activity by in vitro experiments. TGF-β expression was evaluated by immunofluorescence.ResultsAbsolute numbers of Treg cells and BrdU+ Treg cells were increased in LN from experimental compared to normal and control rats. These cells displayed a CD45RC−, CD62L−, Helios+ phenotype. CD4+ CD25bright T cells from TLN of experimental rats were able to suppress T cell-proliferation more efficiently than those derived from normal and control rats. Cells isolated from TLN and ILN expressed TGF-β.Conclusion Our results suggest that Treg cells with a memory/activated phenotype proliferate extensively in the inflamed testis and LN of rats with EAO exhibiting an enhanced suppressive capacity. TGF-β may be involved in their suppressive mechanism.
    American Journal Of Reproductive Immunology 08/2014; 73(2). DOI:10.1111/aji.12312 · 3.32 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Foxp3(+) regulatory T cells (Treg cells) maintain immunological tolerance, and their deficiency results in fatal multiorgan autoimmunity. Although heightened signaling via the T cell antigen receptor (TCR) is critical for the differentiation of Treg cells, the role of TCR signaling in Treg cell function remains largely unknown. Here we demonstrated that inducible ablation of the TCR resulted in Treg cell dysfunction that could not be attributed to impaired expression of the transcription factor Foxp3, decreased expression of Treg cell signature genes or altered ability to sense and consume interleukin 2 (IL-2). Instead, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated Treg cell transcriptional signature. Our results reveal a critical role for the TCR in the suppressor capacity of Treg cells.
    Nature Immunology 09/2014; 15(11). DOI:10.1038/ni.3004 · 24.97 Impact Factor

Preview (3 Sources)

Download
0 Downloads
Available from