Journal
JOURNAL OF IMMUNOLOGY
Volume 190, Issue 6, Pages 2519-2526Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1202104
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Funding
- National Institutes of Health [R01 DK 084246, R01 AI 051448, K08 DK 070924, R21 DK 084568, CA68485, DK20593, DK58404, HD15052, DK59637, EY08126]
- Juvenile Diabetes Research Foundation [APC 4-2007-1056, 1-2008-108]
- Vanderbilt Ingram Cancer Center (National Institutes of Health) [P30 CA68485]
- Vanderbilt Digestive Disease Research Center (National Institutes of Health) [DK058404]
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Autoreactive B lymphocytes that are not culled by central tolerance in the bone marrow frequently enter the peripheral repertoire in a state of functional impairment, termed anergy. These cells are recognized as a liability for autoimmunity, but their contribution to disease is not well understood. Insulin-specific 125Tg B cells support T cell-mediated type 1 diabetes in NOD mice, despite being anergic to B cell mitogens and T cell-dependent immunization. Using this model, the potential of anergic, autoreactive B cells to present Ag and activate T cells was investigated. The data show that 1) insulin is captured and rapidly internalized by 125Tg BCRs, 2) these Ag-exposed B cells are competent to activate both experienced and naive CD4(+) T cells, 3) anergic 125Tg B cells are more efficient than naive B cells at activating T cells when Ag is limiting, and 4) 125Tg B cells are competent to generate low-affinity insulin B chain epitopes necessary for activation of diabetogenic anti-insulin BDC12-4.1 T cells, indicating the pathological relevance of anergic B cells in type 1 diabetes. Thus, phenotypically tolerant B cells that are retained in the repertoire may promote autoimmunity by driving activation and expansion of autoaggressive T cells via Ag presentation. The Journal of Immunology, 2013, 190: 2519-2526.
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