Ligand density determines the efficiency of negative selection in the thymus.
To study the influence of antigen density on the efficiency of negative selection in the thymus, MHC class I (H-2K(b), K(b)) transgenic mice were generated, which expressed a K(b) transgene under the control of its natural promoter at 33% (K(b-lo)) or 150% (K(b-hi)) the surface density of Kb in C57BL/6 (B6, H-2(b)) mice. These mice were crossed to anti-K(b) T-cell receptor (Des-TCR) transgenic mice. In Des-TCRxK(b-hi) double transgenic mice, Des-TCR bearing T cells were completely eliminated during thymocyte maturation. In contrast, in Des-TCRxK(b-lo) double transgenic mice, two populations of Des-TCR T cells were evident, which either expressed the Des-TCR at intermediate density in the absence of CD8 (Des-TCR(int)CD8(-)) or expressed both the Des-TCR and CD8 at low density (Des-TCRloCD8lo). In the thymus of both types of double transgenic mice, no Des-TCR(+)CD4(+)CD8(+) thymocytes were detected, suggesting that deletion of Des-TCR cells occurred before the CD4(+)CD8(+) stage. Because only very few Des-TCR(+) thymocytes were found in Des-TCRxK(b-hi) transgenic mice, deletion of these T cells apparently occurred upon expression of the Des-TCR. By contrast, Des-TCRxK(b-lo) transgenic mice showed distinct populations of Des-TCR(int)CD4-8- and Des-TCR(lo)CD8(lo) thymocytes, suggesting that expression of the CD8 coreceptor was required to allow negative selection to proceed. Functional analyses showed that sublethally irradiated Des-TCRxK(b-lo) double transgenic mice were protected from lethal graft-versus-host disease by injected Des-TCR lymph node cells.
Römermann
D
D
Klinik für Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, D-30623 Hannover, Germany.
Heath
W R
WR
Allison
J
J
Bayer
B
B
Sorge
Y
Y
Miller
J F
JF
Hoffmann
M W
MW
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D003433:Crosses, Genetic; D006085:Graft Survival / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D013997:Time Factors
D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D011948:Receptors, Antigen, T-Cell