Abstract
β Cell replacement via islet or pancreas transplantation is currently the only approach to cure type 1 diabetic patients. Recurrent β cell autoimmunity is a critical factor contributing to graft rejection along with alloreactivity. However, the specificity and dynamics of recurrent β cell autoimmunity remain largely undefined. Accordingly, we compared the repertoire of CD8+ T cells infiltrating grafted and endogenous islets in diabetic nonobese diabetic mice. In endogenous islets, CD8+ T cells specific for an islet-specific glucose-6-phosphatase catalytic subunit-related protein derived peptide (IGRP206-214) were the most prevalent T cells. Similar CD8+ T cells dominated the early graft infiltrate but were expanded 6-fold relative to endogenous islets. Single-cell analysis of the TCR α and β chains showed restricted variable gene usage by IGRP 206-214-specific CD8+ T cells that was shared between the graft and endogenous islets of individual mice. However, as islet graft infiltration progressed, the number of IGRP206-214-specific CD8 + T cells decreased despite stable numbers of CD8+ T cells. These results demonstrate that recurrent β cell autoimmunity is characterized by recruitment to the grafts and expansion of already prevalent autoimmune T cell clonotypes residing in the endogenous islets. Furthermore, depletion of IGRP206-214-specific CD8+ T cells by peptide administration delayed islet graft survival, suggesting IGRP206-214- specific CD8+ T cells play a role early in islet graft rejection but are displaced with time by other specificities, perhaps by epitope spread.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1637-1644 |
| Number of pages | 8 |
| Journal | Journal of Immunology |
| Volume | 176 |
| Issue number | 3 |
| State | Published - Feb 1 2006 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Immunology
Cite this
Early autoimmune destruction of islet grafts is associated with a restricted repertoire of IGRP-specific CD8+ T cells in diabetic nonobese diabetic mice. / Wong, Carmen P.; Li, Li; Frelinger, Jeffrey A; Tisch, Roland.
In: Journal of Immunology, Vol. 176, No. 3, 01.02.2006, p. 1637-1644.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Early autoimmune destruction of islet grafts is associated with a restricted repertoire of IGRP-specific CD8+ T cells in diabetic nonobese diabetic mice
AU - Wong, Carmen P.
AU - Li, Li
AU - Frelinger, Jeffrey A
AU - Tisch, Roland
PY - 2006/2/1
Y1 - 2006/2/1
N2 - β Cell replacement via islet or pancreas transplantation is currently the only approach to cure type 1 diabetic patients. Recurrent β cell autoimmunity is a critical factor contributing to graft rejection along with alloreactivity. However, the specificity and dynamics of recurrent β cell autoimmunity remain largely undefined. Accordingly, we compared the repertoire of CD8+ T cells infiltrating grafted and endogenous islets in diabetic nonobese diabetic mice. In endogenous islets, CD8+ T cells specific for an islet-specific glucose-6-phosphatase catalytic subunit-related protein derived peptide (IGRP206-214) were the most prevalent T cells. Similar CD8+ T cells dominated the early graft infiltrate but were expanded 6-fold relative to endogenous islets. Single-cell analysis of the TCR α and β chains showed restricted variable gene usage by IGRP 206-214-specific CD8+ T cells that was shared between the graft and endogenous islets of individual mice. However, as islet graft infiltration progressed, the number of IGRP206-214-specific CD8 + T cells decreased despite stable numbers of CD8+ T cells. These results demonstrate that recurrent β cell autoimmunity is characterized by recruitment to the grafts and expansion of already prevalent autoimmune T cell clonotypes residing in the endogenous islets. Furthermore, depletion of IGRP206-214-specific CD8+ T cells by peptide administration delayed islet graft survival, suggesting IGRP206-214- specific CD8+ T cells play a role early in islet graft rejection but are displaced with time by other specificities, perhaps by epitope spread.
AB - β Cell replacement via islet or pancreas transplantation is currently the only approach to cure type 1 diabetic patients. Recurrent β cell autoimmunity is a critical factor contributing to graft rejection along with alloreactivity. However, the specificity and dynamics of recurrent β cell autoimmunity remain largely undefined. Accordingly, we compared the repertoire of CD8+ T cells infiltrating grafted and endogenous islets in diabetic nonobese diabetic mice. In endogenous islets, CD8+ T cells specific for an islet-specific glucose-6-phosphatase catalytic subunit-related protein derived peptide (IGRP206-214) were the most prevalent T cells. Similar CD8+ T cells dominated the early graft infiltrate but were expanded 6-fold relative to endogenous islets. Single-cell analysis of the TCR α and β chains showed restricted variable gene usage by IGRP 206-214-specific CD8+ T cells that was shared between the graft and endogenous islets of individual mice. However, as islet graft infiltration progressed, the number of IGRP206-214-specific CD8 + T cells decreased despite stable numbers of CD8+ T cells. These results demonstrate that recurrent β cell autoimmunity is characterized by recruitment to the grafts and expansion of already prevalent autoimmune T cell clonotypes residing in the endogenous islets. Furthermore, depletion of IGRP206-214-specific CD8+ T cells by peptide administration delayed islet graft survival, suggesting IGRP206-214- specific CD8+ T cells play a role early in islet graft rejection but are displaced with time by other specificities, perhaps by epitope spread.
UR - http://www.scopus.com/inward/record.url?scp=31144440201&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=31144440201&partnerID=8YFLogxK
M3 - Article
VL - 176
SP - 1637
EP - 1644
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -