Adaptive tolerance and clonal anergy are distinct biochemical states.
Adaptive tolerance is a process by which T cells become desensitized when Ag stimulation persists following an initial immune response in vivo. To examine the biochemical changes in TCR signaling present in this state, we used a mouse model in which Rag2(-/-) TCR-transgenic CD4(+) T cells were transferred into CD3epsilon(-/-) recipients expressing their cognate Ag. Compared with naive T cells, adaptively tolerant T cells had normal levels of TCR and slightly increased levels of CD4. Following activation with anti-TCR and anti-CD4 mAbs, the predominant signaling block in the tolerant cells was at the level of Zap70 kinase activity, which was decreased 75% in vitro. Phosphorylations of the Zap70 substrates (linker of activated T cells and phospholipase Cgamma1 were also profoundly diminished. This proximal defect impacted mostly on the calcium/NFAT and NF-kappaB pathways, with only a modest decrease in ERK1/2 phosphorylation. This state was contrasted with T cell clonal anergy in which the RAS/MAPK pathway was preferentially impaired and there was much less inhibition of Zap70 kinase activity. Both hyporesponsive states manifested a block in IkappaB degradation. These results demonstrate that T cell adaptive tolerance and clonal anergy are distinct biochemical states, possibly providing T cells with two molecular mechanisms to curtail responsiveness in different biological circumstances.
Chiodetti
Lynda
L
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Choi
Seeyoung
S
Barber
Daniel L
DL
Schwartz
Ronald H
RH
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D017635:Clonal Anergy / Q000276:immunology*; D004789:Enzyme Activation; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; C491734:Lat protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051966:Phospholipase C gamma; D002118:Calcium