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

• Published in: Blood Vol. 116; no. 13; pp. 2266 - 2276
• Main Authors: Fukaya, Tomohiro, Takagi, Hideaki, Sato, Yumiko, Sato, Kaori, Eizumi, Kawori, Taya, Honami, Shin, Tahiro, Chen, Lieping, Dong, Chen, Azuma, Miyuki, Yagita, Hideo, Malissen, Bernard, Sato, Katsuaki
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 30-09-2010; Americain Society of Hematology; American Society of Hematology
• Series: Immunobiology
• Subjects: Administration, Oral; Animals; Antigen Presentation; Antigens; Antigens - administration & dosage; Antigens, CD80; B7-1 Antigen - genetics; B7-1 Antigen - metabolism; B7-H1 Antigen; Biological and medical sciences; Dendritic Cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Forkhead Transcription Factors; Forkhead Transcription Factors - metabolism; Hematologic and hematopoietic diseases; Immune Tolerance; Immunobiology; Immunoglobulin G; Immunoglobulin G - biosynthesis; Immunology; In Vitro Techniques; Life Sciences; Lymph Nodes; Lymph Nodes - cytology; Lymph Nodes - immunology; Medical sciences; Membrane Glycoproteins; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mesentery; Mesentery - cytology; Mesentery - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Ovalbumin; Ovalbumin - administration & dosage; Ovalbumin - immunology; Peptides; Peptides - deficiency; Peptides - genetics; Peptides - metabolism; Programmed Cell Death 1 Ligand 2 Protein; Receptors, Antigen, T-Cell; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Recombinant Proteins; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; T-Lymphocytes, Regulatory; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Dendritic cell; Lymph node; Hematology; Antigen presenting cell; T-Lymphocyte; Tolerance; Antigen specific; Costimulatory molecule; Regulatory cell; B7-H1 molecule
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-10-250472

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.