MHC class I expression and CD8+ T cell development in TAP1/beta 2-microglobulin double mutant mice.
We have bred to homozygosity gene disruptions for the transporter associated with antigen processing 1 (TAP1) and beta 2-microglobulin (beta 2m), each of which plays a distinct role in providing class I MHC subunits. Surface expression of H-2Kb or Db on cells derived from TAP1/beta 2m -/- mice was undetectable by immunofluorescence or immunoprecipitation, unlike the situation observed for TAP1 -/- and beta 2m -/- single mutant mice. Yet, TAP1/beta 2m -/- cells were able to elicit a CD8+ cytotoxic T cell (CTL) response in mice of different H-2 haplotypes and could be killed by anti-H-2b specific CTL. Furthermore, TAP1/beta 2m -/- skin grafts were rejected by bm1 mutant mice. This suggests that very low levels of conformed class I heavy chains can reach the cell surface even in the complete absence of TAP1 and beta 2m gene products, and that these molecules may select a functional CD8+ T cell repertoire. Indeed, CD4-CD8+ T cells were detected in TAP1/beta 2m -/- mice, but in numbers lower than in either of the single mutant mice. Nonetheless, it was possible to elicit a CD8+ allospecific and H-2b reactive CTL response in TAP1/beta 2m -/- mice. In line with this, TAP1/beta 2m -/- mice rapidly rejected TAP1/beta 2m +/- skin grafts. Our results suggest that some MHC class I heavy chains in TAP1/beta 2m -/- cells can reach the cell surface in a form that allows recognition by allospecific CTL and positive selection of CD8+ T cells.
Ljunggren
H G
HG
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139, USA.
Van Kaer
L
L
Sabatine
M S
MS
Auchincloss
H
H
Tonegawa
S
S
Ploegh
H L
HL
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D000939:Epitopes / Q000235:genetics; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007519:Isoantigens / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016038:Skin Transplantation; D001613:beta 2-Microglobulin / Q000235:genetics* / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007519:Isoantigens; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; D001613:beta 2-Microglobulin