CD1d ligation on human monocytes directly signals rapid NF-κB activation and production of bioactive IL-12

Abstract

Natural killer T cells (NKT cells) expressing a semiinvariant CD1d-reactive T cell receptor (invariant NKT, iNKT) can be rapidly activated by monocytes or immature dendritic cells (iDCs) bearing aCD1d-presented glycolipid antigen and can in turn stimulate these myeloid cells to mature and produce IL-12. Previous studies have shown that iNKT-produced IFN␥ and CD40 ligand contribute to this dendritic cell maturation. This study demonstrates that CD1d ligation alone, in the absence of iNKT, could rapidly (within 24 h) stimulate production of bioactive IL-12p70 by CD1d ؉ human peripheral blood monocytes as well as iDCs. IFN␥ alone had no effect, but it markedly enhanced CD1d-stimulated IL-12 production. Monocyte differentiation, as assessed by CD40 and CD1a upregulation, was also accelerated by CD1d stimulation, consistent with this representing a physiological response. CD1d ligation on the human monocytic cell line THP-1 similarly specifically stimulated IL-12 production. Biochemical studies showed that IL-12 release correlated with rapid phosphorylation of I B, a critical step in NF-B activation. Selective NF-B inhibition blocked this CD1d-stimulated IL-12 production. Finally, CD1d ligation could also enhance IL-12 production in the presence of suboptimal LPS or CD40 stimulation. These findings demonstrate an innate immune signaling function for CD1d and provide a mechanism for the rapid activation of monocytes and iDCs by CD1d-reactive T cells.antigen-presenting cell ͉ innate immunity ͉ natural killer T cell C D1d is a nonpolymorphic MHC class I-like protein constitutively expressed by antigen-presenting cells (APC) and by some epithelia, whereas CD1a-c are induced upon dendritic cell (DC) maturation. CD1d is recognized by a subpopulation of T cells, many of which express markers typical of natural killer cells and have been termed natural killer T cells (NKT cells) (1-3). A major fraction of CD1d-restricted T cells recognize CD1d through an invariant T cell receptor (TCR)␣ chain (V␣24-J␣18 in humans). CD1d-reactive NKT cells using this invariant TCR (iNKT) are largely primed in vivo for the rapid production of T helper 1 and T helper 2 cytokines (IFN␥ and IL-4) and have regulatory functions in innate and adaptive immune responses (3, 4). A glycolipid antigen isolated from marine sponge (␣-galactosylceramide, ␣galcer) is recognized by iNKT in the context of CD1d (5-8). In vivo, ␣galcer causes activation of iNKT, rapid cytokine production, and subsequent systemic activation of innate and adaptive immune cells (9, 10).Data from many groups indicate that iNKT functions can be mediated through interactions with CD1d ϩ APC including . Murine studies have shown that iNKT activation can be enhanced by B7 ligation of CD28 and that IL-12 produced by DCs can further enhance iNKT IFN␥ production (11,12,20). Conversely, murine and human studies have shown that iNKT can stimulate the maturation of ␣galcer-pulsed DCs (11,12,18,20). This DC stimulation appears to be mediated by CD40 ligand on the iNKT through ligation of CD40 ...

DX5+NKT cells induce the death of colitis‐associated cells: involvement of programmed death ligand‐1

“…CD62L + NKT cells may be CD1d dependent [38]. It is also notable that our results do not completely rule out the possibility that CD1d blocking antibody may also trigger CD1d, and thus in some way promote inflammatory responses in the gut, especially through CD1d ligation on monocytes, which could enhance inflammation via induction of IL-12 [39]. However, previously published data indicate that CD1d cross-linking on epithelial cells leads rather to the production of barrier-enhancing and immunoregulatory cytokines [40].…”

On/Off TLR Signaling Decides Proinflammatory or Tolerogenic Dendritic Cell Maturation upon CD1d-Mediated Interaction with Invariant NKT Cells

“…Similar to other restriction molecules, CD1d plays additional biological functions, including cell signaling. In fact, several studies demonstrated that CD1d ligation produces activating signals within human monocytes and intestinal intraepithelial cells (60,64). We demonstrated that the CD1d engagement alone produced a tolerogenic signal and induced IL-10 release by immature DCs.…”

“…However, we cannot exclude that, in vivo, iNKT cells with a strongly biased cytokine profile preferentially induce either protolerogenic or proinflammatory DC maturation. For example, high levels of IFN-g and IL-12 released by adjuvant iNKT cells could synergize with the maturation signal transmitted by iNKT cells through cell-cell contact and favor proinflammatory DC maturation (60).…”

NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

“…Cd1d Ϫ/Ϫ C57BL/6 mice were previously reported to have an increased bacterial burden and joint inflammation after syringe infection with B. burgdorferi (30). However, T cells with more diverse TCRs also recognize CD1d; also, CD1d has been reported to have a signaling function that may be independent of T lymphocyte activity (33,34). In fact, in several experimental systems (35)(36)(37), analysis of Cd1d Ϫ/Ϫ and J␣18 Ϫ/Ϫ mice gave discordant results, suggesting either a role for CD1d-reactive T cells with more diverse TCRs or another function for CD1d besides antigen presentation.…”