Batf3-Dependent CD11b^low/− Peripheral Dendritic Cells Are GM-CSF-Independent and Are Not Required for Th Cell Priming After Subcutaneous Immunization

Abstract 1113

Granulocyte/macrophage colony stimulating factor (GM-CSF) regulates the development and activity of several myeloid cell types, including dendritic cells (DCs), thereby influencing the initiation and maintenance of adaptive immune responses. Mice lacking GM-CSF or its receptor show decreased antigen specific T cell priming against the encephalitogenic peptide of myelin oligodendrocyte glycoprotein (MOG_35–55), and are resistant to experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis. Beyond this role in priming adaptive immune responses, GM-CSF acts to sustain ongoing T cell effector responses, both in EAE initiated by MOG_35–55 peptide and in other models of autoimmunity.

A recent report has argued that part of the role for GM-CSF in EAE is based on its requirement for the development of a subset of dermal DCs, termed CD11b^low/−Langerin⁺CD103⁺ DCs (J Exp Med. 207:953–61, 2010). These dermal DCs represent one anatomic subtype of peripheral tissue CD11b^low/−CD103⁺ DCs, and share the properties of efficient antigen cross-presentation and IL-12 production with lymphoid tissue-resident CD8α⁺ DCs. Peripheral tissue CD11b^low/−CD103⁺ DCs and lymphoid tissue-resident CD8α⁺ DCs are developmentally related, each being dependent on FMS-like tyrosine kinase 3 ligand (Flt3L), and requiring the transcription factors Batf3, Irf8, and Id2 for development. Mice deficient in any one of these transcription factors selectively lack these DC subsets, with Batf3^−/− mice representing the best model for studying the role of these DCs in vivo, as Irf8^−/− and Id2^−/− mice display more widespread immune defects.

Here, we directly compared the development of peripheral tissue DCs and susceptibility to EAE in GM-CSF receptor deficient (Csf2rb^−/−) and Batf3^−/− mice. We confirmed that Csf2rb^−/− mice displayed poor priming of MOG_35-55 peptide-specific T cell responses and resisted induction of EAE. Importantly, however, we found that Batf3-dependent dermal CD11b^low/−Langerin⁺ DCs did, in fact, develop in Csf2rb^−/− mice, but that these DCs expressed reduced, but not absent, levels of the surface marker CD103. In contrast, Batf3^−/− mice, lacking all peripheral CD11b^low/− DCs and lymphoid tissue-resident CD8α⁺ DCs, showed robust Th cell priming after subcutaneous immunization, and were fully susceptible to EAE. These results exclude the hypothesis that defective T effector cell priming and resistance to EAE exhibited by Csf2rb^−/− mice result from the absence of dermal CD11b^low/−Langerin⁺CD103⁺ DCs, and instead suggest that GM-CSF is acting via different mechanisms to promote autoimmunity.