Recent publications report that heat shock proteins (HSPs) can endow regulatory responses to the systemic immune system when administered via the mucosal route, leading to an amelioration of atherosclerosis and allergy. However, it remains poorly understood if HSP antigens exist in the luminal contents of the gastrointestinal tract and which types of HSP induce regulatory responses. Here we addressed these problems, considering that numerous gut microflora and foods are natural sources of HSPs. SDS-PAGE and immunoblotting with the anti-HSP60 antibody demonstrated the intact and degraded forms of HSP60 mainly in appendix and large intestine of the gastrointestinal tract. No reactivity with this antibody was observed for any of the luminal contents derived from germ-free animals, suggesting gut microflora to be a source of the intestinal HSPs because of lack of HSPs in animal chow diet. GroEL, a typical member of bacterial HSP60, showed a tendency to stimulate splenocytes in germ-free mice, compared to that in conventional mice, suggesting that resident commensal bacterial GroEL may stimulate HSP-reactive T cells as regulatory cells in conventional animals. Importantly, GroEL, but not mouse-derived HSP60, caused naïve T cells to differentiate into CD4+ CD25+ Foxp3+ T cells, indicating that the production of regulatory T cells depends on the type of HSP. Thus, HSPs derived from commensal microbes can be utilized to stimulate immunoregulatory pathways for the maintenance of intestinal homeostasis.
Two critical periods of maximum exposure to antigens occur in young mammals, immediately after birth and at weaning, as a result of colonization by commensal bacteria and the ingestion of new diets. At weaning, active immune responses of antibody production against dietary proteins are known to occur, but simultaneously, oral tolerance is acquired for harmless food proteins. However, regulated mechanisms of the immune system at weaning remain to be elucidated although its immune responses may be somewhat similar to those in adulthood. Considering that tolerogenic antigen-presenting cells (APCs) are likely to be a key factor in the acquisition of oral tolerance, in the present study, we examined the changes of dendritic cells (DCs) in the lamina propria (LP) on exposure to food proteins at weaning. C57BL/6 female mice were weaned at the age of 3 weeks and orally administered 10 mg of ovalbumin (OVA) for ten consecutive days after weaning. The administration led to a decrease in the plasma level of immunoglobulin specific for OVA, suggesting the acquisition of oral tolerance. The uptake of fluorescence-labeled OVA was significantly observed for CD11c(+)LPDCs. When we analyzed the changes of two types of LPDCs, PDCA-1(+) MHC II(+) DCs and CD103(+) MHC II(+) DCs, ten consecutive gavages of OVA marginally, but not significantly, augmented only the frequency of PDCA-1(+) MHC II(+) DCs. Considering that the change of APCs likely appears immediately on the response to antigen intake, we found the statistically significant increase in the frequency of PDCA-1(+) DCs, but not in that of CD103(+) DCs, even after two treatments, indicating PDCA-1(+) DCs to be recruited in the LP within 2 days of exposure to food proteins. These results suggest that the behavior of tolerogenic PDCA-1(+) DCs may change at weaning with the removal of the immunoprotective components of maternal milk.
Dendritic cell (DC) development begins in the bone marrow and immature progenitors reach their sites of residence in lymphoid organs. The mechanism of DC development in the bone marrow and in peripheral lymphoid organs is poorly understood. Here, we examined the effects of synthetic oligodeoxynucleotides containing a CpG motif (CpG-ODNs) on the development of DC from the bone marrow cells. Approximately 15% of bone marrow cells expressed CD11c surface antigen in the in vitro culture for 8 days in the presence of IL-3. However, the addition of a phosphorothioate-modified CpG-ODN (PTO-CpG-ODN), but not a phosphodiester-modified ODN (PO-CpG-ODN), suppressed the expression of CD11c surface antigen. Also, we examined the effects of CpG-ODNs on the maintenance of DCs resident in the gastrointestinal lymphoid tissues, where immature progenitors may be challenged by a variety of ODN derived from microflora. The population of CD11c(+)B220(int)Gr-1(low) cells decreased by the addition of PTO-CpG-ODN when the lymphocytes from mesenteric lymph nodes as well as spleen are cultured for 2 days in the presence of GM-CSF. In contrast, this population increased in the case of the lymphocytes from Peyer's patches. It thus follows that PTO-CpG-ODN plays a regulatory role in the differentiation of bone marrow cells into DCs and in the functional maintenance of DCs at peripheral lymphoid organs.
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