Direct and indirect cross-tolerance of alloreactive T cells by dendritic cells retained in the immature stage.
BACKGROUND
Rejection of allografts entails the direct and indirect cross-recognition of donor major histocompatibility complex molecules by recipient alloreactive T cells. The ability to manipulate the state of dendritic cell (DC) maturation in vitro has enabled us to induce tolerance specifically targeting the alloreactive T-cell compartment. In this study, the immunoregulatory effect of alloantigen presentation by ex vivo-generated donor and recipient DCs retained in immature stage was investigated.


METHODS
Dendritic cell were generated by culturing monocytes with granulocyte-macrophage colony-stimulating factor and interleukin-4. Ex vivo-generated tolerogenic DCs were characterized by flow cytometry and confocal microscopy. Recipient T-cell responses to donor or recipient DCs loaded with donor-derived apoptotic cells were assessed in a two-step culture system.


RESULTS
Dendritic cells maintained their phagocytic and endocytic activities, and had significantly reduced capacity to prime recipient T cells. Moreover, primary coculture of recipient T cells with donor tolerogenic DCs rendered alloantigen-specific T cells hyporesponsive to a subsequent challenge with donor immunogenic DCs as evidenced by decreased proliferation and cytokine secretion. Importantly, recipient tolerogenic DCs loaded with donor-derived apoptotic cells were able to cross-tolerize recipient T cells. This was revealed by alloantigen-specific T-cell hyporesponsiveness on restimulation with the recipient immunogenic DCs loaded with different tissue-derived apoptotic cells obtained from the same donor.


CONCLUSIONS
Dendritic cells retained in immature stage induce direct and most importantly indirect cross-tolerance of alloantigen-specific T cells. It may be likely that administration of donor and/or recipient DCs could be one means with which to promote tolerance induction in acute and chronic phases of organ transplant.
Nouri-Shirazi
Mahyar
M
Department of Biomedical Sciences, Immunology Laboratory, Baylor College of Dentistry, Texas A&M University System Health Science Center, Dallas, TX 75246, USA. mnshirazi@tambcd.edu.
Guinet
Elisabeth
E
D000111:Acetylcysteine / Q000494:pharmacology; D000917:Antibody Formation; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D017635:Clonal Anergy; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D007108:Immune Tolerance; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
D000941:Antigens; D016207:Cytokines; D016328:NF-kappa B; D000111:Acetylcysteine