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TCR Revision As A Mechanism Of Peripheral Tolerance
Author(s) -
Vaitaitis Gisela M,
Pennock Nathan D,
Baker Rocky L,
Barbour Gene M,
Haskins Kathryn,
Wagner David H
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.669.22
Subject(s) - t cell receptor , nod , autoimmunity , clone (java method) , immunology , t cell , peripheral tolerance , microbiology and biotechnology , biology , cd40 , antigen , immune tolerance , cytotoxic t cell , gene , antibody , genetics , immune system , in vitro
Development of autoaggressive T cells is required to fulminate autoimmune diseases such as type I diabetes. We have demonstrated a mechanism, TCR revision, present in a subset of peripheral T cells, CD4 lo CD40 + , that can alter those T cells to become self‐antigen reactive and that circumvents thymic selective pressures. TCR revision is induced in CD4 lo CD40 + T cells by engagement of CD40 and this is also responsible for expansion of those T cells in autoimmunity. We speculated that an already self‐reactive T cell could, via this mechanism, be driven to further TCR revision and skew antigen recognition away from self‐antigens, thereby inducing tolerance. To address this we used a T cell clone, BDC‐2.5, that rapidly transfers diabetes to NOD.scid animals. Here we demonstrate that if the BDC‐2.5 T cells are CD40 engaged for 4 days prior to transfer into NOD.scid mice, they no longer transfer disease. Early during CD40 stimulation the BDC‐2.5 T cells induce expression and nuclear translocation of recombination activating gene (RAG) proteins that are necessary for TCR revision. RAG‐induction is followed by altered TCR Vα expression but, strikingly, not by altered TCR Vβ expression. The data suggest that agonistic CD40 treatment could be explored as a means of inducing peripheral tolerance and, interestingly, suggest that revision of TCRβ is driven by a different mechanism than revision of TCRα