Batf3-dependent CD103(+) dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice

The role of different DC subsets in priming and maintenance of immunity against Leishmania major (L. major) infection is debated. The transcription factor basic leucine zipper transcription factor, ATF-like 3 (Batf3) is essential for the development of mouse CD103(+) DCs and some functions of CD8(+) DCs. We found that CD103(+) DCs were significantly reduced in the dermis of Batf3-deficient C57BL/6 mice. Batf3(-/-) mice developed exacerbated and unresolved cutaneous pathology following a low dose of intradermal L. major infection in the ear pinnae. Parasite load was increased 1000-fold locally and expanded systemically. Batf3 deficiency did not affect L. major antigen presentation to T cells, which was directly exerted by CD8(-) conventional DCs (cDCs) in the skin draining LN. However, CD4(+) T-cell differentiation in the LN and skin was skewed to nonprotective Treg- and Th2-cell subtypes. CD103(+) DCs are major IL-12 producers during L. major infection. Local Th1 immunity was severely hindered, correlating with impaired IL-12 production and reduction in CD103(+) DC numbers. Adoptive transfer of WT but not IL-12p40(-/-) Batf3-dependent DCs significantly improved anti-L. major response in infected Batf3(-/-) mice. Our results suggest that IL-12 production by Batf3-dependent CD103(+) DCs is crucial for maintenance of local Th1 immunity against L. major infection.We are grateful to members of the Immunobiology of Inflammation lab for discussions and Carlos Ardavin for critical reading of the manuscript. We thank the CNIC Cellomics and Comparative Medicine Units and the technicians and assistants in the Department of Vascular Biology and Inflammation for technical support. We thank Simon Bartlett (CNIC) and Kenneth McCreath for providing English editing. We are indebted to all the scientists who shared reagents with us. Work in the DS laboratory is funded by the CNIC and grants from the Spanish Ministry of Economy and Competitiveness (SAF-2013-42920-R) and the European Research Council (ERC Starting Independent Researcher Grant 2010, ERC-2010-StG 260414). D.S. is the recipient of a Ramon y Cajal fellowship (RYC-2009-04235) from the Spanish Ministry of Economy and Competitiveness. M.M-L. is the recipient of a FPU fellowship (AP2010-5935) from the Spanish Ministry of Education.S