Bim-mediated apoptosis is not necessary for thymic negative selection to ubiquitous self-antigens.
T cell education in the thymus is critical for establishing a functional, yet self-tolerant, T cell repertoire. Negative selection is a key process in enforcing self-tolerance. There are many questions that surround the mechanism of negative selection, but it is currently held that apoptosis initiated by Bim and/or Nur77 is critical for negative selection. Recent studies, however, have questioned the necessity of Bim in maintaining both central and peripheral T cell tolerance. To reconcile these apparently contradictory findings, we examined the role of Bim in negative selection in the well-characterized, physiological HY(cd4) mouse model. We found that while Bim expression was required for CD4(+)CD8(+) double-positive thymocyte apoptosis, it was not required for negative selection. Furthermore, Bim deficiency did not alter the frequency or affinity of male reactive cells that escape negative selection in an oligoclonal repertoire. Collectively, these studies indicate that negative selection occurs efficiently in the absence of apoptosis and suggest that the current paradigm of negative selection requiring apoptosis be revisited.
Hu
Qian
Q
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Sader
Alyssa
A
Parkman
Julia C
JC
Baldwin
Troy A
TA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001324:Autoantigens / Q000096:biosynthesis* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D005260:Female; D006182:H-Y Antigen / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015704:CD4 Antigens; D016827:CD8 Antigens; D006182:H-Y Antigen; D008024:Ligands; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins