Extrathymic deletion of cd8+ alloreactive t cells in a transgenic t cell receptor model of neonatal tolerance

Steven H. Borenstein, Keshung S. Tao, Lori J. West, John W. Chamberlain

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background. Immunological tolerance to foreign antigen is most easily achieved during the neonatal period. Although deletion of T cells has been demonstrated in neonatal tolerance models in which donor and recipient express different MHC class II molecules, the requirement for deletion in MHC class I-disparate models is less clear. To address this issue, we used as recipient the T cell receptor (TCR) transgenic mouse (TgM) strain 2C in which the majority of CD8+ T cells express a single α/β TCR alloreactive to H-2Ld, thus facilitating direct monitoring of the class I alloreactive population. Methods. Newborn (less than 24 hr of age) 2C TgM received injections i.v.with syngeneic C57BL/6J (H-2b) (B6) or semiallogeneic (B6xDBA)F1 (H-2bd; H-2Ld+) splenocytes. Adults were subsequently analyzed in terms of tolerance, deletion of 2C+ T cells, and Research Institute, Programs in Infection/Immunity/Injury and Repair, and Genetics, The Hospital For Sick Children, Toronto, Ontario, Canada M5G 1X8. chimerism. Results. The results showed that semiallogeneic-, but not syngeneic-, injected neonates were unresponsive as adults to H-2Ld-expressing target cells in vitro and the majority of these mice accepted H-2Ld+ skin grafts. Delaying the injection to 72 hr after birth or reducing the number of cells injected essentially abolished in vivo unresponsiveness in 2C recipients. Thus, the 2C TCR Tg model demonstrates the characteristics typical of neonatal tolerance. Injection of 2C neonates within 24 hr of birth with semiallogeneic versus syngeneic cells led to more than a 12-fold reduction of CD8+ 2C+ T cells in adult spleen and LNCs. In contrast, deletion of CD8+ 2C+ cells in adult thymus was not consistently observed. Based on MHC class II expression to distinguish donor (I-E+) and recipient (I-E-) cells, semiallogeneic-injected mice were chimeric in spleens and lymph nodes (LNs). Conclusions. These results demonstrate that neonatal MHC class I tolerance in the adult is associated with low level hematopoietic chimerism and extrathymic deletion of alloreactive CD8+ T cells.

Original languageEnglish (US)
Pages (from-to)1807-1816
Number of pages10
JournalTransplantation
Volume72
Issue number11
StatePublished - Dec 15 2001
Externally publishedYes

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T-Lymphocytes
T-Cell Antigen Receptor
Chimerism
Newborn Infant
Transgenic Mice
Injections
Spleen
Tissue Donors
Parturition
Ontario
Thymus Gland
Canada
Immunity
Cell Count
Lymph Nodes
Transplants
Antigens
Skin
Wounds and Injuries
Infection

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Extrathymic deletion of cd8+ alloreactive t cells in a transgenic t cell receptor model of neonatal tolerance. / Borenstein, Steven H.; Tao, Keshung S.; West, Lori J.; Chamberlain, John W.

In: Transplantation, Vol. 72, No. 11, 15.12.2001, p. 1807-1816.

Research output: Contribution to journalArticle

Borenstein, Steven H. ; Tao, Keshung S. ; West, Lori J. ; Chamberlain, John W. / Extrathymic deletion of cd8+ alloreactive t cells in a transgenic t cell receptor model of neonatal tolerance. In: Transplantation. 2001 ; Vol. 72, No. 11. pp. 1807-1816.
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abstract = "Background. Immunological tolerance to foreign antigen is most easily achieved during the neonatal period. Although deletion of T cells has been demonstrated in neonatal tolerance models in which donor and recipient express different MHC class II molecules, the requirement for deletion in MHC class I-disparate models is less clear. To address this issue, we used as recipient the T cell receptor (TCR) transgenic mouse (TgM) strain 2C in which the majority of CD8+ T cells express a single α/β TCR alloreactive to H-2Ld, thus facilitating direct monitoring of the class I alloreactive population. Methods. Newborn (less than 24 hr of age) 2C TgM received injections i.v.with syngeneic C57BL/6J (H-2b) (B6) or semiallogeneic (B6xDBA)F1 (H-2bd; H-2Ld+) splenocytes. Adults were subsequently analyzed in terms of tolerance, deletion of 2C+ T cells, and Research Institute, Programs in Infection/Immunity/Injury and Repair, and Genetics, The Hospital For Sick Children, Toronto, Ontario, Canada M5G 1X8. chimerism. Results. The results showed that semiallogeneic-, but not syngeneic-, injected neonates were unresponsive as adults to H-2Ld-expressing target cells in vitro and the majority of these mice accepted H-2Ld+ skin grafts. Delaying the injection to 72 hr after birth or reducing the number of cells injected essentially abolished in vivo unresponsiveness in 2C recipients. Thus, the 2C TCR Tg model demonstrates the characteristics typical of neonatal tolerance. Injection of 2C neonates within 24 hr of birth with semiallogeneic versus syngeneic cells led to more than a 12-fold reduction of CD8+ 2C+ T cells in adult spleen and LNCs. In contrast, deletion of CD8+ 2C+ cells in adult thymus was not consistently observed. Based on MHC class II expression to distinguish donor (I-E+) and recipient (I-E-) cells, semiallogeneic-injected mice were chimeric in spleens and lymph nodes (LNs). Conclusions. These results demonstrate that neonatal MHC class I tolerance in the adult is associated with low level hematopoietic chimerism and extrathymic deletion of alloreactive CD8+ T cells.",
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T1 - Extrathymic deletion of cd8+ alloreactive t cells in a transgenic t cell receptor model of neonatal tolerance

AU - Borenstein, Steven H.

AU - Tao, Keshung S.

AU - West, Lori J.

AU - Chamberlain, John W.

PY - 2001/12/15

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N2 - Background. Immunological tolerance to foreign antigen is most easily achieved during the neonatal period. Although deletion of T cells has been demonstrated in neonatal tolerance models in which donor and recipient express different MHC class II molecules, the requirement for deletion in MHC class I-disparate models is less clear. To address this issue, we used as recipient the T cell receptor (TCR) transgenic mouse (TgM) strain 2C in which the majority of CD8+ T cells express a single α/β TCR alloreactive to H-2Ld, thus facilitating direct monitoring of the class I alloreactive population. Methods. Newborn (less than 24 hr of age) 2C TgM received injections i.v.with syngeneic C57BL/6J (H-2b) (B6) or semiallogeneic (B6xDBA)F1 (H-2bd; H-2Ld+) splenocytes. Adults were subsequently analyzed in terms of tolerance, deletion of 2C+ T cells, and Research Institute, Programs in Infection/Immunity/Injury and Repair, and Genetics, The Hospital For Sick Children, Toronto, Ontario, Canada M5G 1X8. chimerism. Results. The results showed that semiallogeneic-, but not syngeneic-, injected neonates were unresponsive as adults to H-2Ld-expressing target cells in vitro and the majority of these mice accepted H-2Ld+ skin grafts. Delaying the injection to 72 hr after birth or reducing the number of cells injected essentially abolished in vivo unresponsiveness in 2C recipients. Thus, the 2C TCR Tg model demonstrates the characteristics typical of neonatal tolerance. Injection of 2C neonates within 24 hr of birth with semiallogeneic versus syngeneic cells led to more than a 12-fold reduction of CD8+ 2C+ T cells in adult spleen and LNCs. In contrast, deletion of CD8+ 2C+ cells in adult thymus was not consistently observed. Based on MHC class II expression to distinguish donor (I-E+) and recipient (I-E-) cells, semiallogeneic-injected mice were chimeric in spleens and lymph nodes (LNs). Conclusions. These results demonstrate that neonatal MHC class I tolerance in the adult is associated with low level hematopoietic chimerism and extrathymic deletion of alloreactive CD8+ T cells.

AB - Background. Immunological tolerance to foreign antigen is most easily achieved during the neonatal period. Although deletion of T cells has been demonstrated in neonatal tolerance models in which donor and recipient express different MHC class II molecules, the requirement for deletion in MHC class I-disparate models is less clear. To address this issue, we used as recipient the T cell receptor (TCR) transgenic mouse (TgM) strain 2C in which the majority of CD8+ T cells express a single α/β TCR alloreactive to H-2Ld, thus facilitating direct monitoring of the class I alloreactive population. Methods. Newborn (less than 24 hr of age) 2C TgM received injections i.v.with syngeneic C57BL/6J (H-2b) (B6) or semiallogeneic (B6xDBA)F1 (H-2bd; H-2Ld+) splenocytes. Adults were subsequently analyzed in terms of tolerance, deletion of 2C+ T cells, and Research Institute, Programs in Infection/Immunity/Injury and Repair, and Genetics, The Hospital For Sick Children, Toronto, Ontario, Canada M5G 1X8. chimerism. Results. The results showed that semiallogeneic-, but not syngeneic-, injected neonates were unresponsive as adults to H-2Ld-expressing target cells in vitro and the majority of these mice accepted H-2Ld+ skin grafts. Delaying the injection to 72 hr after birth or reducing the number of cells injected essentially abolished in vivo unresponsiveness in 2C recipients. Thus, the 2C TCR Tg model demonstrates the characteristics typical of neonatal tolerance. Injection of 2C neonates within 24 hr of birth with semiallogeneic versus syngeneic cells led to more than a 12-fold reduction of CD8+ 2C+ T cells in adult spleen and LNCs. In contrast, deletion of CD8+ 2C+ cells in adult thymus was not consistently observed. Based on MHC class II expression to distinguish donor (I-E+) and recipient (I-E-) cells, semiallogeneic-injected mice were chimeric in spleens and lymph nodes (LNs). Conclusions. These results demonstrate that neonatal MHC class I tolerance in the adult is associated with low level hematopoietic chimerism and extrathymic deletion of alloreactive CD8+ T cells.

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