Loss or mismatch of MHC class I is sufficient to trigger NK cell-mediated rejection of resting lymphocytes in vivo - role of KARAP/DAP12-dependent and -independent pathways.
A prediction from the "missing self" hypothesis is that down-regulation of MHC class I on resting hematopoietic cells should be sufficient to make them susceptible to NK cell killing. Using a method enabling kinetic and quantitative assessments of NK cell-mediated rejection responses in vivo, we here show that resting hematopoietic cells from beta(2)-microglobulin-deficient (beta(2)m(-/-)) mice were rapidly rejected in unmanipulated C57BL/6 (B6) mice. In situations of allelic MHC class I mismatches rejection occurred but required longer time. beta(2)m(-/-) donor cells pre-activated with concanavalin A were more efficiently eliminated compared to resting cells, as were MHC(-) tumor cells. When recipient mice were pretreated with an IFN inducer to activate NK cells, rejection was also enhanced. The signaling adaptor KARAP/DAP12 was dispensable for rejection of beta(2)m(-/-) cells (lacking MHC) but critical for rejection of BALB/c cells (mismatched MHC) in unmanipulated B6 recipients. In contrast, B6 recipients with pre-activated NK cells rejected BALB/c cells in a KARAP/DAP12-independent fashion. Loss or mismatch of MHC class I in resting cells was thus sufficient to convey susceptibility to NK cell rejection. However, activation of the effector or the target enhanced rejection and shifted the balance between different signaling pathways involved.
Oberg
Linda
L
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden. linda.oberg@mtc.ki.se
Johansson
Sofia
S
Michaëlsson
Jakob
J
Tomasello
Elena
E
Vivier
Eric
E
Kärre
Klas
K
Höglund
Petter
P
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D005452:Fluoresceins / Q000737:chemistry; D006183:H-2 Antigens / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D005452:Fluoresceins; D006183:H-2 Antigens; D011971:Receptors, Immunologic; C484963:Tyrobp protein, mouse; D001613:beta 2-Microglobulin; C024098:6-carboxyfluorescein