Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 12, Pages 8278-8287Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.12.8278
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Funding
- The Marianne and Marcus Wallenberg Foundation
- Swedish Science Council (Medicine) [K2000-06X-03382]
- Sahlgrenska University Hospital
- Mucosal Immunology and Vaccine Program at the University of Gothenburg
- government of Sweden
- the Republic of Korea
- Government of Netherlands
- Government of Kuwait
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Mucosal administration of Ag conjugated to cholera toxin B subunit (CTB) can efficiently induce peripheral immunologic tolerance, so-called oral tolerance, associated with development of Foxp3(+)CD25(+)CD4(+) regulatory T (Treg) cells. Using an established sublingual tolerization regimen with Ag(OVA)/CTB conjugate, wherein CTB mediates Ag uptake and presentation by most B lymphocytes irrespective of their Ag specificity, we have assessed the importance of B cells for induction of Ag-specific Treg cells and oral tolerance. We found that Treg cells are reduced in mu MT-/- B cell-deficient mice compared with wild-type (WT) mice. After sublingual Ag/CTB treatment, Treg cells increased much more in WT than in 1zMT-/- mice; however, adoptive transfer of B cells before treatment normalized Treg cell development and functional oral tolerance. B cells from OVA/CTB-treated mice expressed more IL-10 and less CD86 than control B cells. Adoptive transfer of these cells before parenteral immunization with OVA led to efficient suppression of proliferation and to induction of apoptotic depletion of Ag-specific CD25(-)CD4(+) effector T cells associated with the expansion of Treg cells. However, also OVA/CTB-treated mu MT-/- mice could suppress the immune response to parenteral immunization with OVA, which was associated with a strong increase in Foxp3(-)CD4(+) T cells expressing LAP/TGF-beta. Our results indicate that mucosal tolerance comprises at least two separate pathways: one being B cell dependent and associated with expansion of Treg cells and Treg-mediated suppression and depletion of effector T cells, and one being B cell independent and associated with development of Foxp3(-)LAP(+)TGF-beta(+) regulatory T cells. The Journal of Immunology, 2008, 181: 8278-8287.
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