Commensal bacteria trigger a full dendritic cell maturation program that promotes the expansion of non-Tr1 suppressor T cells

Abstract

Dendritic cells (DCs) orchestrate the immune response establishing immunity versus tolerance. These two opposite functions may be dictated by DC maturation status with maturity linked to immunogenicity. DCs directly interact with trillions of noninvasive intestinal bacteria in vivo, a process that contributes to gut homeostasis. We here evaluated the maturation program elicited in human DCs by direct exposure to commensal-related bacteria (CB) in the absence of inflammatory signals. We showed that eight gram(+) and gram(-) CB strains up-regulated costimulatory molecule expression in DCs and provoked a chemokine receptor switch similar to that activated by gram(+) pathogens. CB strains may be classified into three groups according to DC cytokine release: high IL-12 and low IL-10; low IL-12 and high IL-10; and low IL-12 and IL-10. All CB-treated DCs produced IL-1beta and IL-6 and almost no TGF-beta. Yet, CB instructed DCs to convert naive CD4+ T cells into hyporesponsive T cells that secreted low or no IFN-gamma, IL-10, and IL-17 and instead, displayed suppressor function. These data demonstrate that phenotypic DC maturation combined to an appropriate cytokine profile is insufficient to warrant Th1, IL-10-secreting T regulatory Type 1 (Tr1), or Th17 polarization. We propose that commensal flora and as such, probiotics manipulate DCs by a yet-unidentified pathway to enforce gut tolerance.

CD4+ T Cells and Lactobacillus casei Control Relapsing Colitis Mediated by CD8+ T Cells

“…An alternative hypothesis is that L. casei conditioning of mucosal dendritic cells could promote survival and/or function of preexisting Treg or could polarize Tconv into Treg. This is supported by recent in vitro data documenting that human myeloid dendritic cells cultured with L. casei DN-114 001 induce the polarization of Tconv into Treg in vitro (39). Whether L. casei could operate in vivo via professional APC, epithelial cells, or stromal intestinal cells remains to be fully explored.…”

Flexible cytokine production by macrophages and T cells in response to probiotic bacteria: A possible mechanism by which probiotics exert multifunctional immune regulatory activities

“…Alternatively, LcS might be able to induce the development of an as yet unidentified type of Treg cell, which has been shown to be induced by another probiotic strain, L. casei DN-114 001. 38 The fact that LcS induced different types of cytokine responses in Peyer's patch cells and in spleen cells is likely to be of great importance from the viewpoint expression and T cell responses at the intestinal mucosal sites and also at corresponding effecter sites apart from the intestine when LcS is administered in in vivo models with a compromised or excessively activated immune system. Although we are still a long way from unraveling the underlying mechanism by which specific probiotics exert multifunctional immune regulatory activities, we believe that our recent findings, obtained from a series of in vitro studies using macrophages and Peyer's patch cells, will provide a theoretical basis for understanding the mechanism of the sophisticated immune regulation carried out by probiotics.…”

Colorectal carcinoma: Importance of colonic environment for anti-cancer response and systemic immunity

“…Intestinal inflammatory responses induced by pathogenic bacteria are driven by recognition of pathogen-associated molecular patterns (PAMPs) with involvement of Toll-like receptor (TLR) expressed on mucosal cells, mesenchymal cells, and mucosal immune cells. The pro-inflammatory cytokines (i.e., IL-1, IL-6, IL-8, and CCL5) collaborate with the activation of macrophages by lipopolysaccharides to stimulate DC (Macpherson et al, 2005;Baba et al, 2008). After uptake of the pathogenic antigens and migration in the MLN, the DC mature and produce IL-12.…”

“…The IL-10-producing DCs exert their function by migrating in the Peyer's patches and in the MLN where the tolerance to the antigens originating from the alimentary tract is developed. In this way, these DC contribute to the control of the homeostasis in the bowel and permit the maintenance of a tolerant environment leading also to systemic tolerance and local IgA production (Bilsborough and Viney, 2004;Woof and Mestecky, 2005;Baba et al, 2008;Figure 1).…”