T-cell reconstitution without T-cell immunopathology in two models of T-cell-mediated tissue destruction.
Antigen-specific T cells play a pivotal role in adaptive immune responses. However, they also contribute to the progression of a variety of diseases including autoimmune disorders, graft rejection and graft-versus-host disease (GVHD). Non-specific immune-ablation treatments compromise the ability of the host to respond to infection, whereas the selective removal of epitope-specific T cells could theoretically ameliorate T-cell-mediated pathology while preserving the rest of the host immune function. In this study we investigated whether it is possible to destroy specific unwanted antigen-specific T cells by incubating polyclonal T-cell populations with major histocompatibility complex (MHC) tetramers that are conjugated to the ribosomal-inactivating toxin, saporin. This strategy resulted in a dramatic reduction in the number of targeted antigen (Ag)-specific CD8 T cells with no observable bystander toxicity in vitro. Moreover, in a model of transferable T-cell-dependent neurological disease induced by intracerebral (i.c.) lymphocytic choriomeningitis virus (LCMV) infection, the targeted killing of LCMV-specific CD8 T cells extended the survival of mice or fully prevented their death, depending on the dose of cells transferred. In addition, the tetramer- saporin conjugate also reduced liver damage in a model of donor T-cell-mediated hepatic destruction. These data provide a proof of principle that MHC tetramers could be exploited for the elimination or clinical manipulation of T-cell responses by linking effector molecules (a toxin in this case) to MHC tetramers. Also, the results suggest that it may be feasible to remodel T-cell responses, especially in immunocompromised hosts who receive adoptive cell transfers with many potential alloreactive cells.
Penaloza-MacMaster
Pablo
P
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA. ppenalo@emory.edu
Masopust
David
D
Ahmed
Rafi
R
D056704:Adaptive Immunity; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D008212:Lymphocyte Depletion / Q000379:methods*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D054789:Ribosome Inactivating Proteins, Type 1; D000410:Alanine Transaminase; D000076985:Saporins