Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 983 - 993 |
| Number of pages | 11 |
| Journal | European Journal of Immunology |
| Volume | 44 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2014 |
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BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice. / Marino Moreno, Eliana; Walters, Stacey N; Villanueva, Jeanette E; Richards, James L; Mackay, Charles R; Grey, Shane T.
In: European Journal of Immunology, Vol. 44, No. 4, 2014, p. 983 - 993.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice
AU - Marino Moreno, Eliana
AU - Walters, Stacey N
AU - Villanueva, Jeanette E
AU - Richards, James L
AU - Mackay, Charles R
AU - Grey, Shane T
PY - 2014
Y1 - 2014
N2 - Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.
AB - Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.
UR - http://onlinelibrary.wiley.com/doi/10.1002/eji.201344186/pdf
U2 - 10.1002/eji.201344186
DO - 10.1002/eji.201344186
M3 - Article
VL - 44
SP - 983
EP - 993
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 4
ER -