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Increased Foxp3(+) CD4(+) regulatory T cells with intact suppressive activity but altered cellular localization in murine lupus.

ABSTRACT: Foxp3(+) CD4(+) regulatory T (T(reg)) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T(reg) cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T(reg) cells in (NZB x NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T(reg) number and frequency in aged BWF1 mice with developing lupus nephritis were increased, not decreased, and in vitro suppressive activity in lymphoid organs was intact. In addition, T(reg) cells trafficked to target organs because cells were present in the kidney and lung. T(reg) cells of aged BWF1 mice exhibited altered localization within lymph organs, however, and an altered phenotype, with higher expression levels of chemokine receptors and activation markers, suggesting a highly activated cellular state. Notably, the expression levels of co-stimulatory molecules were also markedly enhanced in the T(reg) cells of aged BWF1 mice. Furthermore, T(reg) cells of BWF1 mice did not show any suppressive effects on antibody production in vitro. Taken together, we conclude that T(reg) cells in BWF1 mice are not predisposed to functional incompetence but rather are present in a highly activated state.

SUBMITTER: Abe J

PROVIDER: S-EPMC2626380 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Increased Foxp3(+) CD4(+) regulatory T cells with intact suppressive activity but altered cellular localization in murine lupus.

Abe Jun J Ueha Satoshi S Suzuki Jun J Tokano Yoshiaki Y Matsushima Kouji K Ishikawa Sho S

The American journal of pathology 20081113 6

Foxp3(+) CD4(+) regulatory T (T(reg)) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T(reg) cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T(reg) cells in (NZB x NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T(reg) number and frequency in aged BWF1 mice with ...[more]

PMID: 19008373

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Project description:ObjectiveThe approximately 45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Idd9.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3.Research design and methodsWe used a reductionist approach that involves comparing the fate of a type 1 diabetes-relevant autoreactive CD8(+) T-cell population, specific for residues 206-214 of islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP(206-214)), in noncongenic versus B10 Idd9-congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Idd9.2, and Idd9.3) T-cell receptor (TCR)-transgenic (8.3) NOD mice.ResultsMost of the protective effect of Idd9 against 8.3-CD8(+) T-cell-enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive CD8(+) T-cells. Studies in T- and B-cell-deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell-independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the FoxP3(+)CD4(+)CD25(+) T-cell subset in both TCR-transgenic and nontransgenic mice.ConclusionsA gene(s) within Idd9.1 regulates the development and function of FoxP3(+)CD4(+)CD25(+) regulatory T-cells and, in turn, the activation of CD8(+) effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential.

Dataset Information

Increased Foxp3(+) CD4(+) regulatory T cells with intact suppressive activity but altered cellular localization in murine lupus.

Publications

Increased Foxp3(+) CD4(+) regulatory T cells with intact suppressive activity but altered cellular localization in murine lupus.

Similar Datasets

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