Clonality, activated antigen-specific CD8+ T cells, and development of autoimmune cholangitis in dnTGFβRII mice

Kazuhito Kawata, Guo Xiang Yang, Yugo Ando, Hajime Tanaka, Weici Zhang, Yoshimasa Kobayashi, Koichi Tsuneyama, Patrick S Leung, Zhe Xiong Lian, William M. Ridgway, Aftab A. Ansari, Xiaosong He, M. Eric Gershwin

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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 languageEnglish (US)
Pages (from-to)1094-1104
Number of pages11
JournalHepatology
Volume58
Issue number3
DOIs
StatePublished - Sep 2013

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CD8 Antigens
Cholangitis
Growth Factor Receptors
Transforming Growth Factors
T-Lymphocytes
Biliary Liver Cirrhosis
Adoptive Transfer
Ovalbumin
Gastroenterology

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 journalArticle

Kawata, K, Yang, GX, Ando, Y, Tanaka, H, Zhang, W, Kobayashi, Y, Tsuneyama, K, Leung, PS, Lian, ZX, Ridgway, WM, Ansari, AA, He, X & Gershwin, ME 2013, 'Clonality, activated antigen-specific CD8+ T cells, and development of autoimmune cholangitis in dnTGFβRII mice', Hepatology, vol. 58, no. 3, pp. 1094-1104. https://doi.org/10.1002/hep.26418
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. / Clonality, activated antigen-specific CD8+ T cells, and development of autoimmune cholangitis in dnTGFβRII mice. In: Hepatology. 2013 ; Vol. 58, No. 3. pp. 1094-1104.
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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).",
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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

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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).

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