Abstract
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.
Footnotes
This work was supported by National Institutes of Health Grants R01 DK 084246, R01 AI 051448, K08 DK 070924, and R21 DK 084568, as well as by Juvenile Diabetes Research Foundation Grants APC 4-2007-1056 and 1-2008-108. The Vanderbilt University Medical Center Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (National Institutes of Health Grant P30 CA68485) and the Vanderbilt Digestive Disease Research Center (National Institutes of Health Grant DK058404). The Vanderbilt University Medical Center Cell Imaging Shared Resource is supported by National Institutes of Health Grants CA68485, DK20593, DK58404, HD15052, DK59637, and EY08126.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- HEL
- hen egg lysozyme
- MBS
- m-maleimidobenzoyl-N-hydoxysuccinimide ester
- T1D
- type 1 diabetes.
- Received July 30, 2012.
- Accepted January 1, 2013.
- Copyright © 2013 by The American Association of Immunologists, Inc.