Interleukin 2 production, not the pattern of early T-cell antigen receptor-dependent tyrosine phosphorylation, controls anergy induction by both agonists and partial agonists.
Full activation of T cells requires signaling through the T-cell antigen receptor (TCR) and additional surface molecules interacting with ligands on the antigen-presenting cell. TCR recognition of agonist ligands in the absence of accessory signals frequently results in the induction of a state of unresponsiveness termed anergy. However, even in the presence of costimulation, anergy can be induced by TCR partial agonists. The unique pattern of early receptor-induced tyrosine phosphorylation events induced by partial agonists has led to the hypothesis that altered TCR signaling is directly responsible for the development of anergy. Here we show that anergy induction is neither correlated with nor irreversibly determined by the pattern of early TCR-induced phosphorylation. Rather, it appears to result from the absence of downstream events related to interleukin 2 receptor occupancy and/or cell division. This implies that the anergic state can be manipulated independently of the precise pattern of early biochemical changes following TCR occupancy, a finding with implications for understanding the induction of self-tolerance and the use of partial agonist ligands in the treatment of autoimmune diseases.
Madrenas
J
J
Lymphocyte Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA.
Schwartz
R H
RH
Germain
R N
RN
D000818:Animals; D002455:Cell Division; D017635:Clonal Anergy; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis*; D007739:L Cells; D051379:Mice; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases