Abstract
4-1BB (CD137) is an important T cell activating molecule. Here we report that it also promotes development of a distinct B cell subpopulation co-expressing PDCA-1. 4-1BB is expressed constitutively, and its expression is increased when PDCA-1(+) B cells are activated. We found that despite a high level of surface expression of 4-1BB on PDCA-1(+) B cells, treatment of these cells with agonistic anti-4-1BB mAb stimulated the expression of only a few activation markers (B7-2, MHC II, PD-L2), cytokines (IL-12p40/p70), and chemokines (MCP-1, RANTES), as well as sTNFR1, and the immunosuppressive enzyme, IDO. Although the PDCA-1(+) B cells stimulated by anti-4-1BB expressed MHC II at high levels and took up antigens efficiently, Ig class switching was inhibited when they were pulsed with T-independent (TI) or T-dependent (TD) Ags and adoptively transferred into syngeneic recipients. Furthermore, when anti-4-1BB-treated PDCA-1(+) B cells were pulsed with OVA peptide and combined with Vα2(+)CD4(+) T cells, Ag-specific cell division was inhibited both in vitro and in vivo. Our findings suggest that the 4-1BB signal transforms PDCA-1(+) B cells into propagators of negative immune regulation, and establish an important role for 4-1BB in PDCA-1(+) B cell development and function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / pharmacology*
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Bone Marrow Cells / immunology
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Cell Division / drug effects
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Cell Division / immunology
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Cell Lineage
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Cytokines / biosynthesis
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Cytokines / immunology
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Gene Expression / drug effects
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Gene Expression / immunology
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology
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Immunoglobulin Class Switching / drug effects
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Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
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Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Ovalbumin / pharmacology
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Protein Isoforms / genetics
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Protein Isoforms / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics*
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology
Substances
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Antibodies, Monoclonal
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Cytokines
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Histocompatibility Antigens Class II
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Protein Isoforms
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Ovalbumin
Grants and funding
This study was supported by grants from the National Cancer Center, Korea (NCC1210370-1 and NCC1130720-1) and the National Research Foundation of Korea (NRF2005-0093837 and NRF2006-2004212). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.