Lack of oral tolerance in C3H/HeJ mice.

The gut-associated lymphoid tissue (GALT) is constantly exposed to a variety of Ags and must therefore decipher a large number of distinct signals at all times. Responding correctly to each set of signals is crucial. When the GALT receives signals from the intestinal flora or food Ags, it must induce a state of nonresponsiveness (mucosal tolerance). In contrast, when pathogenic bacteria invade the intestinal mucosa, it is necessary to elicit strong T and B cell responses. The GALT is therefore in the position of constantly fighting intolerance to food and the commensal flora while effectively battling infectious microbes. Determining precisely which type of response to generate in each case is key to the prevention of immune dysregulation and tissue damage.

Section: Tlr Involvement In Responses To Intestinal Agssupporting

confidence: 62%

Preventing Intolerance: The Induction of Nonresponsiveness to Dietary and Microbial Antigens in the Intestinal Mucosa

Smith

Nagler‐Anderson

2005

“…Oral tolerance is mediated primarily by TGF-␤1, as anti-TGF-␤1 neutralizing Ab abrogates tolerance induction (69). Moreover, LPS-mediated signaling through the TLR-4 is thought to be obligatory for the induction of oral tolerance, because it was found to be absent in C3H/HeJ mice that are defective in LPS responses due to mutations within the TLR-4 gene (71,72).…”

Section: Discussionmentioning

confidence: 99%

B Cells Activated by Lipopolysaccharide, But Not By Anti-Ig and Anti-CD40 Antibody, Induce Anergy in CD8+ T Cells: Role of TGF-β1

Parekh

Prasad

Banerjee

et al. 2003

202

140

B cells recognize Ag through their surface IgRs and present it in the context of MHC class II molecules to CD4+ T cells. Recent evidence indicates that B cells also present exogenous Ags in the context of MHC class I to CD8+ T cells and thus may play an important role in the modulation of CTL responses. However, in this regard, conflicting reports are available. One group of studies suggests that the interaction between B cells and CD8+ T cells leads to the activation of the T cells, whereas other studies propose that it induces T cell tolerance. For discerning this dichotomy, we used B cells that were activated with either LPS or anti-Ig plus anti-CD40 Ab, which mimic the T-independent and T-dependent modes of B cell activation, respectively, to provide accessory signals to resting CD8+ T cells. Our results show that, in comparison with anti-Ig plus anti-CD40 Ab-activated B cells, the LPS-activated B cells (LPS-B) failed to induce significant levels of proliferation, cytokine secretion, and cytotoxic ability of CD8+ T cells. This hyporesponsiveness of CD8+ T cells activated with LPS-B was significantly rescued by anti-TGF-β1 Ab. Moreover, it was found that such hyporesponsive CD8+ T cells activated with LPS-B had entered a state of anergy. Furthermore, LPS-B expresses a significantly higher level of TGF-β1 on the surface, which caused the observed hyporesponsiveness of CD8+ T cells. Therefore, this study, for the first time, provides a novel mechanism of B cell surface TGF-β1-mediated hyporesponsiveness leading to anergy of CD8+ T cells.

“…Mice that lack a constant source of LPS entering their liver (germfree mice) have reduced expression of the adhesion molecule ICAM-1 in their livers, and a normal level of expression can be restored by the intragastric inoculation of cecal microflora from normal mice (20). Both germfree mice and TLR-4-deficient mice (21) show defective oral tolerance, whereas other studies show that the liver is involved in this process (22,23).…”

Section: A Ctivated Cd8mentioning

confidence: 99%

TLR-4 Regulates CD8+ T Cell Trapping in the Liver

John

Crispe

2005

Mammalian TLRs are understood primarily as an activating system for innate and adaptive immunity, but have also been implicated in sensing cellular damage and in promoting intestinal integrity. In this study we show that TLR-4 also controls the in vivo distribution of activated CD8+ T cells. The liver is a site for trapping and apoptosis of activated CD8+ T cells during systemic immune responses, but the reason for this is unknown. In this study we tested the hypothesis that the liver’s constant exposure to endotoxin, derived from commensal bacteria in the gut, acts via TLR-4 to promote activated T cell adhesion. In the absence of TLR-4, the liver was compromised in its ability to sequester activated CD8+ T cells, and there was an inverse correlation between the frequency of activated CD8+ T cells trapped in the liver and their frequency in the circulating pool. Thus, in the absence of any inflammation, TLR-4 ligands play a significant role in the ability of the liver to trap activated CD8+ T cells. This provides a new perspective on the regulation of immune responses by TLR-4 under basal conditions.