The Regulation of Oral Tolerance by Intestinal Macrophages Utilizes Two Distinct Pathways Involving either CD11b or CX3CR1

Intestinal tolerance requires the priming of FoxP3⁺ regulatory T cells (Tregs) in the mesenteric lymph nodes (mLNs) by CD103⁺ dendritic cells and subsequent homing of Tregs to the intestine. Signaling by resident CD11b⁺CX3CR1^high macrophages present in the intestinal lamina propria leads to further Treg expansion.

Similarly to our previously published data concerning CX3CR1, we show that the deficiency of CD11b leads to a defect in the development of oral tolerance. Adoptive transfer experiments into CD11b^-/- mice showed that, like in CX3CR1^-/- mice, Treg cells were readily induced in the mLNs but local Treg expansion in the lamina propria was reduced.

As signaling via resident macrophages is critical for the expansion of Tregs in the intestinal lamina propria we investigated the pathways that are altered in intestinal macrophages due to CX3CR1 and CD11b deficiency. Surprisingly, microarray analysis revealed that the lack of CD11b and CX3CR1 lead to distinct transcriptomic changes in the intestinal macrophage compartment. Our preliminary data suggest a partial deficiency in TLR signaling in macrophages of CD11b^-/- mice in contrast to macrophages from CX3CR1^-/- mice which exhibit an impairment of IL-10 signaling.

We hypothesize that independent signaling pathways involving either CD11b or CX3CR1 contribute to the tolerogenic function of intestinal macrophages.