Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction

doi:10.1016/0092-8674(91)90163-S

Cell

Volume 65, Issue 2, 19 April 1991, Pages 293-304

https://doi.org/10.1016/0092-8674(91)90163-S Get rights and content

Abstract

By generating two types of transgenic mice we have investigated how extrathymic events can contribute to self tolerance. The major histocompatibility complex class I gene K^b was expressed under the control of the glial fibrillary acidic protein promoter in cells of neuroectodermal origin outside the thymus. These mice were tolerant to K^b. When crossed to transgenic mice expressing a K^b-specific T cell receptor (TCR), clonotype⁺, CD8⁺CD4⁻ mature T cells could be detected in normal numbers in the thymus of the double-transgenic mice but were strongly reduced in spleen and lymph nodes in comparison with TCR single-transgenic mice. After isolation of clonotype negative splenic T cells and activation in vitro, reappearance of the clonotype⁺, CD8⁺CD4⁻ cells was observed. These results indicate that down-regulation of TCR and CD8 molecules on the antigen-specific T cells is a novel mechanism, by which peripheral tolerance to this antigen can occur.

References (60)

B. Arnold et al.
Cytolytic T cells recognize the two amino-terminal domains of H-2 antigens in tandem in influenza A infected cells
Cell
(1984)
L.J. Berg et al.
The effects of MHC gene dosage and allelic variation on T cell receptor selection
Cell
(1990)
A. Bignami et al.
Localisation of the glial fibrillary acidic protein in astrocytes by immunofluorescence
Brain Res.
(1972)
M. Bradbury
Lymphatics and the central nervous system
Trends Neurosci.
(1981)
C. Cowing
Does T cell restriction to la limit the need for self tolerance?
Immunol. Today
(1985)
J.W. Kappler et al.
T cell tolerance by clonal elimination in the thymus
Cell
(1987)
S. Kuhlmann-Krieg et al.
Ultrastructural features of cultured oligodendrocytes expressing stage-specific cell-surface antigens
Dev. Brain Res.
(1988)
L.A. Lampson
Molecular basis of the immune response to neural antigens
Trends Neurosci.
(1987)
D. Lo et al.
Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells
Cell
(1988)
J.R. Parnes et al.
Structure of wild-type and mutant mouse β₂-microglobulin genes
Cell
(1982)

L.M. Roman et al.

The expression of influenza virus hemagglutinin in the pancreatic β cells of transgenic mice results in autoimmune diabetes

Cell

(1990)

N. Sarvetnick et al.

Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma

Cell

(1988)

J. Sprent et al.

Antigen-presenting cells for unprimed T cells

Immunol. Today

(1989)

J. Trotter et al.

Cells positive for the O4 surface antigen isolated by sorting are able to differentiate into astrocytes or oligodendrocytes

Dev. Brain Res.

(1989)

T.E. Adams et al.

Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic β cells

Nature

(1987)

F. Albert et al.

Interaction between MHC-encoded products and cloned T cells. I. Fine specificity of induction of proliferation and lysis

Immunogenetics

(1982)

J. Allison et al.

Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic β cells

Nature

(1988)

B.P. Babbitt et al.

Binding of immunogenic peptides to la histocompatibility molecules

Nature

(1985)

R.E. Billingham et al.

“Actively acquired tolerance” of foreign cells

Nature

(1953)

R.L. Bjorkman et al.

Structure of the human class I histocompatibility antigen, HLA-A2

Nature

(1987)

J. Böhme et al.

Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant

Science

(1989)

T.J. Braciale et al.

Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes

Immunol. Rev.

(1987)

L.C. Burkly et al.

T cell tolerance by clonal anergy in transgenic mice with nonlymphoid expression of MHC class II I-E

Nature

(1989)

F.M. Burnet

The clonal selection theory of acquired immunity

(1959)

J. Chelly et al.

Transcription of the dystrophin gene in human muscle and non-muscle tissues

Nature

(1988)

D.P. Dialynas et al.

Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK 1.5: similarity of L3T4 to the human $Leu3 T4$ molecule

J. Immunol.

(1983)

D.A. Hafler et al.

T cells in multiple sclerosis and inflammatory central nervous system diseases

Immunol. Rev.

(1987)

W.L. Havran et al.

Expression and function of the CD3-antigen receptor on murine CD4⁺8⁺ thymocytes

Nature

(1987)

B. Hogan et al.

C. Hua et al.

Monoclonal antibodies against an H-2K^b-specific cytotoxic T cell clone detect several clone-specific molecules

J. Immunol.

(1986)

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Cell

ArticleDown-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction

Abstract

Cell

Cell

Brain Res.

Trends Neurosci.

Immunol. Today

Cell

Dev. Brain Res.

Trends Neurosci.

Cell

Cell

Cell

Cell

Immunol. Today

Dev. Brain Res.

Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic β cells

Nature

Interaction between MHC-encoded products and cloned T cells. I. Fine specificity of induction of proliferation and lysis

Immunogenetics

Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic β cells

Nature

Binding of immunogenic peptides to la histocompatibility molecules

Nature

“Actively acquired tolerance” of foreign cells

Nature

Structure of the human class I histocompatibility antigen, HLA-A2

Nature

Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant

Science

Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes

Immunol. Rev.

T cell tolerance by clonal anergy in transgenic mice with nonlymphoid expression of MHC class II I-E

Nature

The clonal selection theory of acquired immunity

Transcription of the dystrophin gene in human muscle and non-muscle tissues

Nature

Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK 1.5: similarity of L3T4 to the human Leu3T4 molecule

J. Immunol.

T cells in multiple sclerosis and inflammatory central nervous system diseases

Immunol. Rev.

Expression and function of the CD3-antigen receptor on murine CD4+8+ thymocytes

Nature

Monoclonal antibodies against an H-2Kb-specific cytotoxic T cell clone detect several clone-specific molecules

J. Immunol.

Article
Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction

Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK 1.5: similarity of L3T4 to the human $Leu3 T4$ molecule

Expression and function of the CD3-antigen receptor on murine CD4⁺8⁺ thymocytes

Monoclonal antibodies against an H-2K^b-specific cytotoxic T cell clone detect several clone-specific molecules