Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.
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.
Zhou
T
T
Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, USA.
Cheng
J
J
Yang
P
P
Wang
Z
Z
Liu
C
C
Su
X
X
Bluethmann
H
H
Mountz
J D
JD
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D017637:Clonal Deletion; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D017634:Self Tolerance; D017384:Sequence Deletion; D016176:T-Lymphocyte Subsets; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D017252:CD3 Complex; D004268:DNA-Binding Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors