IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions.
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.
Wan
Suigui
S
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA..
Xia
Changqing
C
Morel
Laurence
L
D000818:Animals; D018122:B7-1 Antigen / Q000032:analysis; D051940:B7-2 Antigen / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D015850:Interleukin-6 / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6