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The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen

Academic Article
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Overview

related to degree

  • Redmond, William, Ph.D. in Biology, Scripps Research 1999 - 2004

authors

  • Redmond, William
  • Wei, C. H.
  • Kreuwel, H. T. C.
  • Sherman, Linda

publication date

  • April 2008

journal

  • Journal of Immunology  Journal

abstract

  • The maintenance of T cell tolerance in the periphery proceeds through several mechanisms, including anergy, immuno-regulation, and deletion via apoptosis. We examined the mechanism underlying the induction of CD8 T cell peripheral tolerance to a self-Ag expressed on pancreatic islet beta-cells. Following adoptive transfer, Ag-specific clone 4 T cells underwent deletion independently of extrinsic death receptors, including Fas, TNFR1, or TNFR2. Additional experiments revealed that the induction of clone 4 T cell apoptosis during peripheral tolerance occurred via an intrinsic death pathway that could be inhibited by overexpression of Bcl-2 or targeted deletion of the proapoptotic molecule, Bim, thereby resulting in accumulation of activated clone 4 T cells. Over-expression of Bcl-2 in clone 4 T cells promoted the development of effector function and insulitis whereas Bim-/- clone 4 cells were not autoaggressive. Examination of the upstream molecular mechanisms contributing to clone 4 T cell apoptosis revealed that it proceeded in a p53, E2F1, and E2F2-independent manner. Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism.

subject areas

  • Animals
  • Antigen Presentation
  • Antigens, CD95
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Autoantigens
  • CD8-Positive T-Lymphocytes
  • Clonal Deletion
  • Fingolimod Hydrochloride
  • Glucose
  • Immunosuppressive Agents
  • Insulin-Secreting Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Propylene Glycols
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Self Tolerance
  • Sphingosine
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 18390708
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Additional Document Info

start page

  • 5275

end page

  • 5282

volume

  • 180

issue

  • 8

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