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PMID: 8666944 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.

The Journal of experimental medicine ·Vol. 183 ·No. 4 ·1996-04-01 ·Pages 1879-92

Zhou T, Cheng J, Yang P, Wang Z, Liu C, Su X, Bluethmann H, Mountz JD

Abstract

The Nur77/Nurr1 family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)-mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (deltaNur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-beta enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8+ thymocytes mediated by CD3/TCR signaling was greatly inhibited in the deltaNur77 Tg mice, compared with non-Tg littermates, after treatment with anti-CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self-reactive T cells was investigated in deltaNur77-Db/HY TCR-alpha/beta double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-alpha/beta in the deltaNur77-TCR-alpha/beta double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8+ thymocytes that expressed Tg TCR-alpha/beta. There was an eightfold increase in the CD8+, Db/HY TCR-alpha/beta T cells in the lymph nodes (LN) of delta Nur77-Db/HY TCR-alpha/beta double Tg compared with Db/HY TCR-alpha/beta Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of deltaNur77-Db/HY TCR-alpha/beta double male mice. These results indicate that inhibition of Nur77/Nurr1 DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen.

MeSH Terms
Animals Apoptosis Base Sequence CD3 Complex CD4-Positive T-Lymphocytes CD8-Positive T-Lymphocytes Clonal Deletion Cytotoxicity, Immunologic DNA-Binding Proteins/genetics,metabolism Female Lymphocyte Activation Lymphocyte Depletion Male Mice Mice, Inbred C57BL Mice, Mutant Strains Mice, Transgenic Molecular Sequence Data Nuclear Receptor Subfamily 4, Group A, Member 1 Receptors, Antigen, T-Cell Receptors, Cytoplasmic and Nuclear Receptors, Steroid Self Tolerance Sequence Deletion T-Lymphocyte Subsets Transcription Factors/genetics,metabolism
Chemicals
CD3 Complex DNA-Binding Proteins Nr4a1 protein, mouse Nuclear Receptor Subfamily 4, Group A, Member 1 Receptors, Antigen, T-Cell Receptors, Cytoplasmic and Nuclear Receptors, Steroid Transcription Factors
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Zhou T
Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, USA.
Cheng J
Yang P
Wang Z
Liu C
Su X
Bluethmann H
Mountz J D
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.183.4.1879
Published
1996-04-01
Pages
1879-92
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2192482
Subset
IM
Grants
NIAMS NIH HHS · P01 AR03555 · United States
NIAID NIH HHS · P50 AI23694 · United States
NIAMS NIH HHS · P60 AR20614 · United States
External Links
PubMed source DOI: 10.1084/jem.183.4.1879 PMC Full Text View journal details
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