Functional avidity directs T-cell fate in autoreactive CD4+ T cells.
Major histocompatibility complex class II tetramer staining and activation analysis identified 2 distinct types of antigen-specific CD4+ T cells in the peripheral blood of humans with type 1 (autoimmune) diabetes. T cells with low-avidity recognition of peptide-MHC ligands had low sensitivity to activation and inefficient activation-induced apoptosis. In contrast, high-avidity T cells were highly sensitive to antigen-induced cell death through apoptotic mechanisms, and both apoptosis-resistant high- and low-avidity T cells that survived prolonged tetramer treatment were rendered anergic to restimulation by antigen. In addition, however, apoptosis-resistant high-avidity T cells acquired regulatory features, being able to suppress both antigen-specific and nonspecific CD4+ T-cell responses. This suppression was contact-dependent and correlated with the down-regulation of HLA class II and costimulatory molecules on antigen-presenting cells, including B cells and dendritic cells. T cells face a variety of fates following antigen exposure, including the paradoxic maintenance of high-avidity autoreactive T cells in the peripheral circulation, perhaps due to this capability of acquiring anergic and suppressive properties. Regulation via down-modulation of antigen-presenting cell function, a form of cell-to-cell licensing for suppression, also offers possibilities for the application of peptide-MHC therapeutics.
Mallone
Roberto
R
Benaroya Research Institute at Virginia Mason, 1201 Ninth Ave, Seattle, WA 98101, USA.
Kochik
Sharon A
SA
Reijonen
Helena
H
Carson
Bryan
B
Ziegler
Steven F
SF
Kwok
William W
WW
Nepom
Gerald T
GT
D000293:Adolescent; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D010641:Phenotype; D011485:Protein Binding; D013379:Substrate Specificity
D000941:Antigens