Abstract
There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8+ T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1-/- recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8+ T cells or due to the abnormal TGFβR environment within which CD8+ T cells were generated. To address this mechanistic issue, we used our dnTGFβRII, OT-I/Rag1-/-, OT-II/Rag1-/- mice and in addition generated OT-I/dnTGFβRII/Rag1-/-, and OT-II/dnTGFβRII/Rag1-/- mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8+ or CD4+ T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1-/- mice and/or OT-II/dnTGFβRII/Rag1-/- mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8+ T cells from dnTGFβRII mice but not CD8+ T cells from OT-I/Rag1-/- mice or from OT-I/dnTGFβRII/Rag1-/- mice transferred disease. These data were not secondary to an absence of CD4+ T cell help since a combination of CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- and CD4+ T cells from OT II/dnTGFβRII/Rag1-/- or CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- with CD4+ T cells from OT-II/Rag1-/- mice failed to transfer disease. Conclusion: Defective TGFβRII signaling, in addition to clonal CD8+ T cells that target biliary cells, are required for induction of autoimmune cholangitis. (Hepatology 2013;53:1094-1104).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1094-1104 |
| Number of pages | 11 |
| Journal | Hepatology |
| Volume | 58 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 2013 |
Fingerprint
ASJC Scopus subject areas
- Hepatology
Cite this
Clonality, activated antigen-specific CD8+ T cells, and development of autoimmune cholangitis in dnTGFβRII mice. / Kawata, Kazuhito; Yang, Guo Xiang; Ando, Yugo; Tanaka, Hajime; Zhang, Weici; Kobayashi, Yoshimasa; Tsuneyama, Koichi; Leung, Patrick S; Lian, Zhe Xiong; Ridgway, William M.; Ansari, Aftab A.; He, Xiaosong; Gershwin, M. Eric.
In: Hepatology, Vol. 58, No. 3, 09.2013, p. 1094-1104.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Clonality, activated antigen-specific CD8+ T cells, and development of autoimmune cholangitis in dnTGFβRII mice
AU - Kawata, Kazuhito
AU - Yang, Guo Xiang
AU - Ando, Yugo
AU - Tanaka, Hajime
AU - Zhang, Weici
AU - Kobayashi, Yoshimasa
AU - Tsuneyama, Koichi
AU - Leung, Patrick S
AU - Lian, Zhe Xiong
AU - Ridgway, William M.
AU - Ansari, Aftab A.
AU - He, Xiaosong
AU - Gershwin, M. Eric
PY - 2013/9
Y1 - 2013/9
N2 - There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8+ T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1-/- recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8+ T cells or due to the abnormal TGFβR environment within which CD8+ T cells were generated. To address this mechanistic issue, we used our dnTGFβRII, OT-I/Rag1-/-, OT-II/Rag1-/- mice and in addition generated OT-I/dnTGFβRII/Rag1-/-, and OT-II/dnTGFβRII/Rag1-/- mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8+ or CD4+ T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1-/- mice and/or OT-II/dnTGFβRII/Rag1-/- mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8+ T cells from dnTGFβRII mice but not CD8+ T cells from OT-I/Rag1-/- mice or from OT-I/dnTGFβRII/Rag1-/- mice transferred disease. These data were not secondary to an absence of CD4+ T cell help since a combination of CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- and CD4+ T cells from OT II/dnTGFβRII/Rag1-/- or CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- with CD4+ T cells from OT-II/Rag1-/- mice failed to transfer disease. Conclusion: Defective TGFβRII signaling, in addition to clonal CD8+ T cells that target biliary cells, are required for induction of autoimmune cholangitis. (Hepatology 2013;53:1094-1104).
AB - There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8+ T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1-/- recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8+ T cells or due to the abnormal TGFβR environment within which CD8+ T cells were generated. To address this mechanistic issue, we used our dnTGFβRII, OT-I/Rag1-/-, OT-II/Rag1-/- mice and in addition generated OT-I/dnTGFβRII/Rag1-/-, and OT-II/dnTGFβRII/Rag1-/- mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8+ or CD4+ T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1-/- mice and/or OT-II/dnTGFβRII/Rag1-/- mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8+ T cells from dnTGFβRII mice but not CD8+ T cells from OT-I/Rag1-/- mice or from OT-I/dnTGFβRII/Rag1-/- mice transferred disease. These data were not secondary to an absence of CD4+ T cell help since a combination of CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- and CD4+ T cells from OT II/dnTGFβRII/Rag1-/- or CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- with CD4+ T cells from OT-II/Rag1-/- mice failed to transfer disease. Conclusion: Defective TGFβRII signaling, in addition to clonal CD8+ T cells that target biliary cells, are required for induction of autoimmune cholangitis. (Hepatology 2013;53:1094-1104).
UR - http://www.scopus.com/inward/record.url?scp=84883244892&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883244892&partnerID=8YFLogxK
U2 - 10.1002/hep.26418
DO - 10.1002/hep.26418
M3 - Article
C2 - 23532950
AN - SCOPUS:84883244892
VL - 58
SP - 1094
EP - 1104
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 3
ER -