title: Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB.
abstract: Acquisition of self-tolerance in the thymus requires T cells to discriminate strong versus weak T cell receptor binding by self-peptide-MHC complexes. We find this discrimination is reported by expression of the transcription factor Helios, which is induced during negative selection but decreases during positive selection. Helios and the proapoptotic protein Bim were coinduced in 55% of nascent CCR7(-) CD4(+) CD69(+) thymocytes. These were short-lived cells that up-regulated PD-1 and down-regulated CD4 and CD8 during Bim-dependent apoptosis. Helios and Bim were also coinduced at the subsequent CCR7(+) CD4(+) CD69(+) CD8(-) stage, and this second wave of Bim-dependent negative selection involved 20% of nascent cells. Unlike CCR7(-) counterparts, Helios(+) CCR7(+) CD4(+) cells mount a concurrent Card11- and c-Rel-dependent activation response that opposes Bim-mediated apoptosis. This "hollow" activation response consists of many NF-κB target genes but lacks key growth mediators like IL-2 and Myc, and the thymocytes were not induced to proliferate. These findings identify Helios as the first marker known to diverge during positive and negative selection of thymocytes and reveal the extent, stage, and molecular nature of two distinct waves of clonal deletion in the normal thymus.
authors: Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors: Stephen R
authors: SR
authors: Daley
authors: Daniel Y
authors: DY
authors: Hu
authors: Christopher C
authors: CC
authors: Goodnow
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D000072224:Bcl-2-Like Protein 11; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D017637:Clonal Deletion / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000096:biosynthesis* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis* / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism; D017634:Self Tolerance; D014157:Transcription Factors / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; C515371:Ccr7 protein, mouse; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D054400:Receptors, CCR7; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse