Adams et al. identified Etv3 as a dendritic cell-intrinsic regulator of immune tolerance. Etv3 is induced during DC maturation and expressed in tissue-derived migratory DCs (migDCs). Etv3 cooperated with NF-κB to promote homeostatic migDC maturation and CCR7-dependent migration. Etv3 deficiency impaired migDC migration and induced upregulation of costimulatory molecules (including OX40L), driving dysfunctional CD25low Treg expansion, spontaneous T cell activation, and multi-organ inflammation. Loss of Etv3 worsened TLR7-driven systemic lupus erythematosus (SLE)-like disease, consistent with observations in human SLE.
Contributed by Shishir Pant
ABSTRACT: Dendritic cells (DCs) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DCs, including tissue-derived migratory DCs (migDCs), and facilitates their homeostatic maturation and CCR7-dependent migration. Mice with global or DC-specific deletion of Etv3 manifested the expansion of CD25(low) regulatory T (T(reg)) cells, spontaneous activation of conventional T cells, and multiorgan T cell infiltration. Etv3 deficiency exacerbated TLR7-driven systemic lupus erythematosus (SLE)-like disease, supporting the reported genetic association of human ETV3 with SLE. Etv3-deficient migDCs up-regulated multiple costimulatory molecules, including OX40 ligand (OX40L/TNFSF4), whose blockade partially rescued the T(reg) cell abnormalities. These results identify Etv3 as an essential regulator of the tolerogenic function of DCs and implicate it in the regulation of human autoimmunity.
Author Info: (1) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (2) Department of Pathology, New York University Grossman School of Medicine, New Y
Author Info: (1) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (2) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (3) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, USA. (4) Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, USA. (5) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (6) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (7) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (8) Department of Surgery, New York University Grossman School of Medicine, New York, NY, USA. (9) Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, USA. (10) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (11) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (12) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (13) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (14) Department of Physics, Ben Gurion University of the Negev, Beer-Sheva, Israel. Ilse Katz Institute for Nanoscale Science and Technology, Ben Gurion University of the Negev, Beer-Sheva, Israel. (15) Cellular Analytics Laboratory, New York University Grossman School of Medicine, New York, NY, USA. Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (16) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (17) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (18) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (19) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, USA. (20) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.
