NF-kappa B is required for the positive selection of CD8+ thymocytes.
To examine the role of NF-kappaB in T cell development, we analyzed thymocyte ontogeny in transgenic (mutant I-kappaBalpha (mI-kappaBalpha)) mice that express a superinhibitory form of the NF-kappaB inhibitory protein, I-kappaBalpha (I-kappaBalpha(A32/36)), under the control of the T cell-specific CD2 promoter and enhancer. Thymi from mI-kappaBalpha mice contained increased numbers of double-positive (DP) and decreased numbers of both CD4(+) and CD8(+) single-positive cells, consistent with a block in DP thymocyte maturation. In addition, expression of CD69, a marker of positive selection, was decreased on DP thymocytes from the mI-kappaBalpha mice. To test directly whether NF-kappaB was required for positive or negative selection, we generated mI-kappaBalpha mice expressing the H-Y or 2C alphabeta TCR transgenes. Expression of the I-kappaBalpha(A32/36) transgene caused a block in the positive selection of CD8(+) single-positive cells in both strains of TCR transgenic animals. In contrast, negative selection was unaffected by expression of the I-kappaBalpha(A32/36) transgene. Taken together, these results identified a NF-kappaB-dependent transcriptional pathway that is selectively required for the positive selection of CD8(+) thymocytes.
Hettmann
T
T
Laboratory of Cardiovascular Biology, Harvard School of Public Health, Boston, MA 02115, USA.
Leiden
J M
JM
D000818:Animals; D021461:Animals, Outbred Strains; D015704:CD4 Antigens / Q000096:biosynthesis / Q000235:genetics; D016827:CD8 Antigens / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D006182:H-Y Antigen / Q000235:genetics; D020672:I-kappa B Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D019076:Transgenes / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D006182:H-Y Antigen; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000072000:NF-KappaB Inhibitor alpha