Induction of tolerance in CD8+ T cells to a transgenic autoantigen expressed in the liver does not require cross-presentation.
Cross-presentation of normal self and candidate tumor Ags by bone marrow (BM)-derived APCs that have not been activated has been demonstrated as a major mechanism contributing to acquisition of tolerance by mature T cells that first encounter an Ag in the periphery (cross-tolerance). Following adoptive transfer of naive TCR-transgenic CD8(+) T cells into a host expressing a transgenic Ag that is a potentially targetable tumor Ag in normal hepatocytes as a self-Ag, we found that the majority of Ag-specific CD8(+) T cells were deleted, with the remaining cells rendered anergic. Studies in BM chimeric mice and with purified cell populations demonstrated that these events were not dependent on cross-presentation by BM-derived APCs including Kupffer cells or liver sinusoidal endothelial cells, and apparently can occur entirely as a consequence of direct recognition of Ag endogenously processed and presented by hepatocytes. Direct recognition of Ag-expressing hepatocytes in vivo induced a proliferative response and up-regulation of activation markers in responding CD8(+) T cells, but proliferating cells did not accumulate, with most cells rapidly eliminated, and the persisting T cells lost the capacity to proliferate in response to repeated Ag stimulation. The results suggest that parenchymal tissues may retain the capacity to directly regulate in vivo responses to self-Ags processed and presented in the context of class I MHC molecules.
Morimoto
Junko
J
Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Tan
Xiaoxio
X
Teague
Ryan M
RM
Ohlén
Claes
C
Greenberg
Philip D
PD
D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005622:Friend murine leukemia virus / Q000276:immunology; D015683:Gene Products, gag / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000276:immunology* / Q000378:metabolism*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D012709:Serum Albumin / Q000235:genetics / Q000276:immunology
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D012709:Serum Albumin