Dendritic cell-specific disruption of TGF-β receptor II leads to altered regulatory T cell phenotype and spontaneous multiorgan autoimmunity

In vitro data and transgenic mouse models suggest a role for TGF-β signaling in dendritic cells (DCs) to prevent autoimmunity primarily through maintenance of DCs in their immature and tolerogenic state characterized by low expression of MHC class II (MHCII) and costimulatory molecules and increased...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2012-10, Vol.189 (8), p.3878-3893
Main Authors: Ramalingam, Rajalakshmy, Larmonier, Claire B, Thurston, Robert D, Midura-Kiela, Monica T, Zheng, Song Guo, Ghishan, Fayez K, Kiela, Pawel R
Format: Article
Language:English
Subjects:
Animals
Autoimmune Diseases - genetics
Autoimmune Diseases - pathology
Autoimmune Diseases - prevention & control
Colitis - genetics
Colitis - immunology
Colitis - prevention & control
Dendritic Cells - immunology
Dendritic Cells - metabolism
Dendritic Cells - pathology
Disease Models, Animal
Immune Tolerance - genetics
Immunophenotyping
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Organ Specificity - genetics
Organ Specificity - immunology
Protein-Serine-Threonine Kinases - deficiency
Protein-Serine-Threonine Kinases - physiology
Receptors, Transforming Growth Factor beta - deficiency
Receptors, Transforming Growth Factor beta - physiology
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
T-Lymphocytes, Regulatory - pathology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In vitro data and transgenic mouse models suggest a role for TGF-β signaling in dendritic cells (DCs) to prevent autoimmunity primarily through maintenance of DCs in their immature and tolerogenic state characterized by low expression of MHC class II (MHCII) and costimulatory molecules and increased expression of IDO, among others. To test whether a complete lack of TGF-β signaling in DCs predisposes mice to spontaneous autoimmunity and to verify the mechanisms implicated previously in vitro, we generated conditional knockout (KO) mice with Cre-mediated DC-specific deletion of Tgfbr2 (DC-Tgfbr2 KO). DC-Tgfbr2 KO mice die before 15 wk of age with multiorgan autoimmune inflammation and spontaneous activation of T and B cells. Interestingly, there were no significant differences in the expression of MHCII, costimulatory molecules, or IDO in secondary lymphoid organ DCs, although Tgfbr2-deficient DCs were more proinflammatory in vitro and in vivo. DC-Tgfbr2 KO showed attenuated Foxp3 expression in regulatory T cells (Tregs) and abnormal expansion of CD25(-)Foxp3(+) Tregs in vivo. Tgfbr2-deficient DCs secreted elevated levels of IFN-γ and were not capable of directing Ag-specific Treg conversion unless in the presence of anti-IFN-γ blocking Ab. Adoptive transfer of induced Tregs into DC-Tgfbr2 KO mice partially rescued the phenotype. Therefore, in vivo, TGF-β signaling in DCs is critical in the control of autoimmunity through both Treg-dependent and -independent mechanisms, but it does not affect MHCII and costimulatory molecule expression.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1201029