TY - JOUR
T1 - Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3 + regulatory T cells in the establishment of oral tolerance
AU - Fukaya, Tomohiro
AU - Takagi, Hideaki
AU - Sato, Yumiko
AU - Sato, Kaori
AU - Eizumi, Kawori
AU - Taya, Honami
AU - Shin, Tahiro
AU - Chen, Lieping
AU - Dong, Chen
AU - Azuma, Miyuki
AU - Yagita, Hideo
AU - Malissen, Bernard
AU - Sato, Katsuaki
PY - 2010/9/30
Y1 - 2010/9/30
N2 - Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to fed antigens. However, the molecular mechanism mediating oral tolerance remains unclear. In this study, we examined the role of the B7 family members of costimulatory molecules in the establishment of oral tolerance. Deficiencies of B7-H1 and B7-DC abrogated the oral tolerance, accompanied by enhanced antigen-specific CD4+ T-cell response and IgG1 production. Mesenteric lymph node (MLN) dendritic cells (DCs) displayed higher levels of B7-H1 and B7-DC than systemic DCs, whereas they showed similar levels of CD80, CD86, and B7-H2. MLN DCs enhanced the antigen-specific generation of CD4 +Foxp3+ inducible regulatory T cells (iTregs) from CD4+Foxp3- T cells rather than CD4+ effector T cells (Teff) relative to systemic DCs, owing to the dominant expression of B7-H1 and B7-DC. Furthermore, the antigen-specific conversion of CD4+Foxp3- T cells into CD4+Foxp3+ iTregs occurred in MLNs greater than in peripheral organs during oral tolerance under steady-state conditions, and such conversion required B7-H1 and B7-DC more than other B7 family members, whereas it was severely impaired under inflammatory conditions. In conclusion, our findings suggest that B7-H1 and B7-DC expressed on MLN DCs are essential for establishing oral tolerance through the de novo generation of antigen-specific CD4+Foxp3+ iTregs.
AB - Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to fed antigens. However, the molecular mechanism mediating oral tolerance remains unclear. In this study, we examined the role of the B7 family members of costimulatory molecules in the establishment of oral tolerance. Deficiencies of B7-H1 and B7-DC abrogated the oral tolerance, accompanied by enhanced antigen-specific CD4+ T-cell response and IgG1 production. Mesenteric lymph node (MLN) dendritic cells (DCs) displayed higher levels of B7-H1 and B7-DC than systemic DCs, whereas they showed similar levels of CD80, CD86, and B7-H2. MLN DCs enhanced the antigen-specific generation of CD4 +Foxp3+ inducible regulatory T cells (iTregs) from CD4+Foxp3- T cells rather than CD4+ effector T cells (Teff) relative to systemic DCs, owing to the dominant expression of B7-H1 and B7-DC. Furthermore, the antigen-specific conversion of CD4+Foxp3- T cells into CD4+Foxp3+ iTregs occurred in MLNs greater than in peripheral organs during oral tolerance under steady-state conditions, and such conversion required B7-H1 and B7-DC more than other B7 family members, whereas it was severely impaired under inflammatory conditions. In conclusion, our findings suggest that B7-H1 and B7-DC expressed on MLN DCs are essential for establishing oral tolerance through the de novo generation of antigen-specific CD4+Foxp3+ iTregs.
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U2 - 10.1182/blood-2009-10-250472
DO - 10.1182/blood-2009-10-250472
M3 - Article
C2 - 20574047
AN - SCOPUS:77957732349
SN - 0006-4971
VL - 116
SP - 2266
EP - 2276
JO - Blood
JF - Blood
IS - 13
ER -