Cutting edge: thymic selection and autoreactivity are regulated by multiple coreceptors involved in T cell activation.
Immune responses are shaped by several processes that promote responses to pathogens and hinder responses to self. One mechanism that contributes to this polarization in response is negative selection, in which thymocytes that can respond to self-peptide/MHC complexes are deleted from the T cell repertoire. I found here that several coreceptors known to contribute to mature T cell activation also participate in negative selection. Interestingly, these molecules appeared to act in a cooperative fashion. Blocking the contribution of these molecules in fetal thymus organ culture not only prevented negative selection in the CD4+ lineage, but also induced the appearance of autoreactive thymocytes. This is the first demonstration that blocking coreceptor interactions during thymic development can produce autoreactive T cells. The contribution of negative selection to the mature T cell repertoire and to autoimmunity is discussed in light of these results.
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DM
Department of Biology, Cancer Center, University of California at San Diego, La Jolla 92093, USA. dpage@ucsd.edu
D000818:Animals; D019138:Antibodies, Blocking / Q000502:physiology; D001324:Autoantigens / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018956:CD5 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005333:Fetus; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D019138:Antibodies, Blocking; D001324:Autoantigens; D018106:CD28 Antigens; D018956:CD5 Antigens; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor