IL-12/IL-23 independent function of Batf3-dependent dendritic cells is required for initiation of disease in a mouse model of vitiligo

Vitiligo is an IFN-ɣ-dependent autoimmune skin disease that causes depigmentation, and we used a mouse model of vitiligo to investigate the role of the Batf3 transcription factor in disease. Batf3 is required for the survival of a small subset of dendritic cells (DCs) known as type 1 classical DCs (cDC1) (identifiable in mice by CD103 and CD8a expression), which are primarily found within epithelial tissues and associated lymph nodes where they provide crucial contributions to pathogen defense, tumor surveillance, and peripheral inflammation. Specifically, Batf3-dependent DCs are significant producers of IL-12, which is necessary for defense against Toxoplasma gondii and Leishmania major ( Martínez‐López et al., 2015 Martínez‐López M. Iborra S. Conde‐Garrosa R. Sancho D. Batf3‐dependent CD103+ dendritic cells are major producers of IL‐12 that drive local Th1 immunity against Leishmania major infection in mice. Eur. J. Immunol. 2015; 45: 119-129 Crossref PubMed Scopus (0) Google Scholar ; Mashayekhi et al., 2011 Mashayekhi M. Sandau M.M. Dunay I.R. Frickel E.M. Khan A. Goldszmid R.S. et al. CD8α+ Dendritic Cells Are the Critical Source of Interleukin-12 that Controls Acute Infection by Toxoplasma gondii Tachyzoites. Immunity. 2011; 35: 249-259 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ). Cross-presentation by Batf3-dependent DCs within lymph nodes is important for surveillance of live, immunogenic tumors, and local chemokine production by Batf3-dependent DCs within tumors significantly increases T cell recruitment ( Hildner et al., 2008 Hildner K. Edelson B.T. Purtha W.E. Diamond M. Matsushita H. Kohyama M. et al. Batf3 Deficiency Reveals a Critical Role for CD8α + Dendritic Cells in Cytotoxic T Cell Immunity. Science. 2008; 322: 1097-1100 Crossref PubMed Scopus (0) Google Scholar ; Roberts et al., 2016 Roberts E.W. Broz M.L. Binnewies M. Headley M.B. Nelson A.E. Wolf D.M. et al. Critical Role for CD103 + /CD141 + Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell. 2016; 30: 324-336 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ; Spranger et al., 2017 Spranger S. Dai D. Horton B. Gajewski T.F. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017; 31 (e4): 711-723 Abstract Full Text Full Text PDF PubMed Scopus (908) Google Scholar ). Batf3-dependent DCs also contribute to autoinflammation. A mouse model of cutaneous lupus erythematosus reported that Batf3-dependent DCs promote CD4+ T cell activation and recruitment to skin ( Ali et al., 2018 Ali N. Zirak B. Truong H.-A. Maurano M.M. Gratz I.K. Abbas A.K. et al. Skin-Resident T Cells Drive Dermal Dendritic Cell Migration in Response to Tissue Self-Antigen. J. Immunol. 2018; 200: 3100-3108 Crossref Scopus (10) Google Scholar ), and we hypothesized that Batf3-dependent DCs may also contribute to vitiligo.