CD 1d‐mediated lipid presentation by CD 11c ⁺ cells regulates intestinal homeostasis

Abstract

Intestinal homeostasis relies on a continuous dialogue between the commensal bacteria and the immune system. Natural killer T (NKT) cells, which recognize CD1d‐restricted microbial lipids and self‐lipids, contribute to the regulation of mucosal immunity, yet the mechanisms underlying their functions remain poorly understood. Here, we demonstrate that NKT cells respond to intestinal lipids and CD11c+ cells (including dendritic cells (DCs) and macrophages) are essential to mediate lipid presentation within the gut ultimately controlling intestinal NKT cell homeostasis and activation. Conversely, CD1d and NKT cells participate in the control of the intestinal bacteria composition and compartmentalization, in the regulation of the IgA repertoire and in the induction of regulatory T cells within the gut. These changes in intestinal homeostasis require CD1d expression on DC/macrophage populations as mice with conditional deletion of CD1d on CD11c+ cells exhibit dysbiosis and altered immune homeostasis. These results unveil the importance of CD11c+ cells in controlling lipid‐dependent immunity in the intestinal compartment and reveal an NKT cell–DC crosstalk as a key mechanism for the regulation of gut homeostasis.

The interaction between invariant Natural Killer T cells and the mucosal microbiota

“…70 The changes in the intestinal microbiota seen in the CD1d-deficient animals could be replicated in mice where CD1d was selectively missing on CD11c + cells. 46 In contrast, in mice with a CD11c-specific deletion of CD1d, the separation between the intestinal bacteria and the epithelial cells was intact, as in the control animals. 46 This demonstrates that iNKT cells influence the intestinal microbiota in at least two independent ways involving CD11c + cells, presumably dendritic cells, and other CD1d + cells in the intestine.…”

“…68 Whereas in control mice the intestinal bacteria were largely separated from the intestinal epithelial cells by a mucus layer, this layer was impaired in the CD1d-deficient animals, leading to a direct contact of the bacteria and the epithelial cells. 46 The impact of iNKT cells on the intestinal microbiota was stronger in the small than the large intestine, 46,69 in line with the higher frequency of iNKT cells in the small intestine. 33 This might also explain why an analysis of faeces from CD1d-deficient pigs did not reveal any differences in the bacterial composition.…”

“…125 CD1d-deficient mice show changes in their IgA-repertoire compared with wild-type mice, but it was suggested that this is not due to a direct interaction with iNKT cells, but rather a consequence of the altered microbial flora in the CD1d À/À mice. 46 However, it was reported that human iNKT cells could stimulate IgA and IgG secretion by B cells in vitro even in the absence of exogenous iNKT cell antigens.…”

“…33,35 Second, using Nur77 expression as an indication for TCR-mediated activation, a CD1d-dependent stimulation of iNKT cells in the intestine was shown in the presence of the intestinal microbiota. 46 Third, intra-gastric administration of GF mice with a mixture of heat-killed bacteria leads to the expression of CD1d-antigen complexes, detected with the antibody clone L363, 47 on liver dendritic cells. 48 Finally, and most directly, iNKT cell antigens have been discovered in several bacteria present in the intestinal microbiota.…”

“…48 Importantly, the interaction between the commensal microbiota and iNKT cells is mutual, as iNKT cells can influence the composition of the intestinal microflora. CD1d-deficient mice were found to host an altered gut microbiota, 46,68,69 which was pro-inflammatory upon transfer into wild-type animals. 69 Furthermore, CD1d-deficient mice were more susceptible to intestinal colonization by pathogenic bacteria as well.…”