| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
The B6.Sle1.Sle2.Sle3 triple congenic mouse (B6.TC) is a model of lupus coexpressing the three major NZM2410-derived susceptibility loci on a C57BL/6 background. B6.TC mice produce high titers of antinuclear nephrogenic autoantibodies and a highly penetrant glomerulonephritis. Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (Treg) and that Sle3 results in intrinsic defects of myeloid cells that hyperactivate T cells. In this report, we show that B6.TC dendritic cells (DCs) accumulate in lymphoid organs and present a defective maturation process, in which bone marrow-derived, plasmacytoid, and myeloid DCs express a significantly lower level of CD80, CD86, and MHC class II. B6.TC DCs also induce a higher level of proliferation in CD4+ T cells than B6 DCs, and B6.TC DCs block the suppressive activity of Treg. B6.TC DCs overproduce IL-6, which is necessary for the blockade of Treg activity, as shown by the effect of anti-IL-6 neutralizing Ab in the suppression assays. The overproduction of IL-6 by DCs and the blockade of Treg activity maps to Sle1, which therefore not only confers a reduced number of Treg but also blocks their ability to regulate autoreactive T cells. Taken together, these results provide a genetic and mechanistic evidence for systemic autoimmunity resulting from an impaired regulatory T cell compartment in both number and function and for Sle1-expressing DCs playing a major role in the latter defect though their production of IL-6.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grant RO1-AI045050 (to L.M.).
2 Address correspondence and reprint requests to Dr. Laurence Morel, Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610-0275. E-mail address: morel{at}ufl.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; pDC, plasmacytoid DC; MDC, myeloid DC; CD4+CD25+ Treg, regulatory T cell; BM, bone marrow; Teff, effector T cell.
This article has been cited by other articles:
|
|
 |
|
  S. G. Zheng, J. Wang, and D. A. Horwitz Cutting Edge: Foxp3+CD4+CD25+ Regulatory T Cells Induced by IL-2 and TGF-{beta} Are Resistant to Th17 Conversion by IL-6 J. Immunol., June 1, 2008; 180(11): 7112 - 7116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A La Cava T-regulatory cells in systemic lupus erythematosus Lupus, May 1, 2008; 17(5): 421 - 425. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Tzankov, C. Meier, P. Hirschmann, P. Went, S. A. Pileri, and S. Dirnhofer Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma Haematologica, February 1, 2008; 93(2): 193 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Cuda, S. Wan, E. S. Sobel, B. P. Croker, and L. Morel Murine Lupus Susceptibility Locus Sle1a Controls Regulatory T Cell Number and Function through Multiple Mechanisms J. Immunol., December 1, 2007; 179(11): 7439 - 7447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chen, S. Vodanovic-Jankovic, B. Johnson, M. Keller, R. Komorowski, and W. R. Drobyski Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease Blood, November 15, 2007; 110(10): 3804 - 3813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Vallois, C. H. Grimm, P. Avner, C. Boitard, and U. C. Rogner The Type 1 Diabetes Locus Idd6 Controls TLR1 Expression J. Immunol., September 15, 2007; 179(6): 3896 - 3903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Deshpande, I. L. King, and B. M. Segal Cutting Edge: CNS CD11c+ Cells from Mice with Encephalomyelitis Polarize Th17 cells and Support CD25+CD4+ T cell-Mediated Immunosuppression, Suggesting Dual Roles in the Disease Process J. Immunol., June 1, 2007; 178(11): 6695 - 6699. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
