IRF8-dependent migratory CD103+CD11b- dendritic cells are required for intestinal intraepithelial lymphocyte homeostasis

CD103⁺CD11b^- IRF8 dependent dendritic cells (DCs) represent one of the major migratory DC subsets in the intestinal mucosa however their role in intestinal immune homeostasis remains unknown. To assess this we generated CD11c-Cre.Irf8^fl/fl mice which lacked CD103⁺CD11b^- DCs in the small intestine and draining mesenteric lymph nodes (MLN) and had normal numbers of migratory CD103⁺CD11b⁺ intestinal DCs. CD11c-Cre.Irf8^fl/fl mice displayed a dramatic reduction in ‘conventional’ small intestinal CD8αβ⁺TCRαβ⁺ intraepithelial lymphocytes (IEL), one of the major pools of conventional tissue resident memory T cells in the body. In contrast numbers of ‘natural’ CD8αα⁺TCRαβ⁺ and CD8αα⁺TCRγδ⁺ IEL remained relatively unperturbed. In an adoptive transfer model, CD8αβ⁺ ovalbumin (OVA) -specific OT-I cells primed in the MLN of CD11c-Cre.Irf8^fl/fl mice expressed reduced levels of the gut homing receptors CCR9 and α4β7 and the homing of these cells to the intestinal epithelium was severely compromised. CD11c-Cre.Irf8^fl/fl mice also completely lacked CD4⁺CD8αα⁺ IEL a population of conventional CD4⁺ T cells that have acquired ‘CD8 T cell like’ CTL activity. Using mixed bone marrow chimeras we found that expression of the TGFβ convertase αvβ8 integrin by intestinal CD103⁺CD11b^- DCs was critical for the generation of CD4⁺CD8αα⁺ IEL. Notably the intestine of Irf8^-/wt mice, which lack lymph node-resident but not intestinal derived IRF8 dependent DCs, had a normal IEL subset composition. Collectively our results demonstrate a non-redundant role for migratory CD103⁺CD11b^- DCs in intestinal intraepithelial lymphocyte homeostasis.