Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2893 - 2905 |
| Number of pages | 13 |
| Journal | Diabetes |
| Volume | 61 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2012 |
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B-cell cross-presentation of autologous antigen precipitates diabetes. / Marino, Eliana; Tan, Bernice; Binge, Lauren C; Mackay, Charles R; Grey, Shane T.
In: Diabetes, Vol. 61, No. 11, 2012, p. 2893 - 2905.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - B-cell cross-presentation of autologous antigen precipitates diabetes
AU - Marino, Eliana
AU - Tan, Bernice
AU - Binge, Lauren C
AU - Mackay, Charles R
AU - Grey, Shane T
PY - 2012
Y1 - 2012
N2 - For autoimmune conditions like type 1 diabetes to progress, self reactive CD8+ T cells would need to interact with peptidea-antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I-restricted fashion. However, the mechanisms by which autoantigen is cross-presented remain to be identified. In this study, we show cross-presentation of islet-derived autoantigens by B cells. B cells engage self-reactive CD8+ T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B+interferon-g+lysosomal-associated membrane protein 1+ effector cells. B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking. Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8+ T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation. Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cella-dependent, interleukin-21-expressing Vb4+CD4+ T cells. Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8+ T cells. Diabetes 61:1-13, 2012
AB - For autoimmune conditions like type 1 diabetes to progress, self reactive CD8+ T cells would need to interact with peptidea-antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I-restricted fashion. However, the mechanisms by which autoantigen is cross-presented remain to be identified. In this study, we show cross-presentation of islet-derived autoantigens by B cells. B cells engage self-reactive CD8+ T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B+interferon-g+lysosomal-associated membrane protein 1+ effector cells. B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking. Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8+ T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation. Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cella-dependent, interleukin-21-expressing Vb4+CD4+ T cells. Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8+ T cells. Diabetes 61:1-13, 2012
UR - http://www.ncbi.nlm.nih.gov/pubmed/22829452
U2 - 10.2337/db12-0006
DO - 10.2337/db12-0006
M3 - Article
VL - 61
SP - 2893
EP - 2905
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 11
ER -