Abstract
Splenic dendritic cells (DCs) present blood-borne antigens to lymphocytes to promote T cell and antibody responses. The cues involved in positioning DCs in areas of antigen exposure in the spleen are undefined. Here we show that CD4(+) DCs highly express EBI2 and migrate to its oxysterol ligand, 7α,25-OHC. In mice lacking EBI2 or the enzymes needed for generating normal distributions of 7α,25-OHC, CD4(+) DCs are reduced in frequency and the remaining cells fail to situate in marginal zone bridging channels. The CD4(+) DC deficiency can be rescued by LTβR agonism. EBI2-mediated positioning in bridging channels promotes DC encounter with blood-borne particulate antigen. Upon exposure to antigen, CD4(+) DCs move rapidly to the T-B zone interface and promote induction of helper T cell and antibody responses. These findings establish an essential role for EBI2 in CD4(+) DC positioning and homeostasis and in facilitating capture and presentation of blood-borne particulate antigens. DOI:http://dx.doi.org/10.7554/eLife.00757.001.
Highlights
Dendritic cells (DCs) play a crucial role in presenting antigens to T cells to initiate adaptive immune responses (Banchereau and Steinman, 1998)
Based on soluble antigen immunization studies and antigen targeting to DC subtypes using antibodies, as well as studies in mice deficient in DC subsets, CD4+ and double negative (DN) DCs have been most strongly implicated in priming CD4 T cell responses against exogenous antigens whereas CD8+ DCs have a more prominent role in crosspresenting antigens and promoting CD8 T cell responses (Pooley et al, 2001; Dudziak et al, 2007; Hildner et al, 2008)
Analysis of isotype switched (IgG1 and IgG2b) plasma cell numbers showed they were more strongly affected (15- to 30-fold reduced) than IgM plasma cells (∼7-fold reduced, Figure 7D,E). These findings provide strong evidence that EBI2 function in DCs is needed for mounting normal CD4 T cell-dependent B cell responses
Summary
Dendritic cells (DCs) play a crucial role in presenting antigens to T cells to initiate adaptive immune responses (Banchereau and Steinman, 1998). Based on soluble antigen immunization studies and antigen targeting to DC subtypes using antibodies, as well as studies in mice deficient in DC subsets, CD4+ and DN DCs have been most strongly implicated in priming CD4 T cell responses against exogenous antigens whereas CD8+ DCs have a more prominent role in crosspresenting antigens and promoting CD8 T cell responses (Pooley et al, 2001; Dudziak et al, 2007; Hildner et al, 2008). These functional distinctions are not strict with some studies, for example, suggesting that CD8+ DCs contribute to priming of CD4+ T cell responses (Tamura et al, 2005; Fukaya et al, 2012)
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