A population of in vivo anergized T cells with a lower activation threshold for the induction of CD25 exhibit differential requirements in mobilization of intracellular calcium and mitogen-activated protein kinase activation.
Chronic exposure of mature T cells with specificity for self-Ags can lead to the induction of a nonfunctional state which is referred to as T cell anergy. It is unclear whether anergic T cells are destined for cell death and thereby harmless or whether they can contribute to the induction of autoimmunity and/or regulation of anti-self reactivity. We have begun to address this issue. In a recent study, we showed that a population of mature CD4-CD8- T cells that express a transgenic TCR specific for the Ld MHC class I molecule are rendered anergic in Ld-expressing mice. In this study, we show that this population of anergic T cells possess a lower activation threshold for the induction of CD25 and CD69 in response to stimulation by antigenic ligands. Furthermore, these anergic T cells undergo extensive proliferation when stimulated with a low-affinity ligand in the presence of an exogenous source of IL-2. Biochemical analysis of the early intracellular signaling events of these in vivo anergized T cells showed that they have a signaling defect at the level of ZAP-70 and linker for the activation of T cell (LAT) phosphorylation. They also exhibit a defect in mobilization of intracellular calcium in response to TCR signaling. However, these anergic T cells demonstrate no defect in SLP-76 phosphorylation and extracellular signal-regulated kinase 1/2 activation. These biochemical characteristics of the anergic T cells were associated with an elevated level of Fyn, but not Lck expression. The potential contributions of these anergic T cells in the induction and/or regulation of autoimmune responses are discussed.
Utting
O
O
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Teh
S J
SJ
Teh
H S
HS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D017635:Clonal Anergy / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D007376:Interleukin-2 / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D037181:Lectins, C-Type; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002118:Calcium; D002352:Carrier Proteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D007376:Interleukin-2; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D014443:Tyrosine; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens; C491734:Lat protein, mouse; C092947:SLP-76 signal Transducing adaptor proteins; C497262:Zap70 protein, mouse