Induction of B-cell immune tolerance by antigen-modified cytotoxic T lymphocytes.
BACKGROUND
Third-party-specific cytotoxic T lymphocytes (CTL), or veto CTL, are being assessed as a cellular therapeutic for the induction of T-cell tolerance during transplantation. Conceptually, veto cell-expressed antigens (Ags) may induce B-cell immune responses, and this may have deleterious consequences. Whether veto cells induce immunity, tolerance, or are ignored by B lymphocytes has, however, not been addressed.


METHODS
CTL were retrovirally transduced with a model cell surface Ag to generate veto CTL. The impact of CTL-specific Ag expression on the activation and tolerization of Ag-specific B cells was assessed in vitro and, using adoptive transfer models, in vivo.


RESULTS
In vitro, CTL-expressed Ag induced an abortive proliferative response in specific B lymphocytes, whereby an initial proliferative burst was followed by cell death. In vivo, the administration of veto CTL also induced B-cell tolerance. Specific immunoglobulin was not detected after subsequent immunization with a veto cell-expressed Ag. Modeling of this effect with Ag-specific B-cell receptor transgenic B lymphocytes demonstrated that Ag-specific B cells were eliminated by the veto CTL; the cell division was accompanied by the exhaustion and depletion of responding cells. Veto-induced B-cell tolerance could be wholly abrogated by treatment with the toll-like receptor ligand lipopolysaccharide, implying that this tolerance resulted from the absence of adequate supplemental signals during antigenic stimulation.


CONCLUSIONS
Veto CTL are effective promoters of B-cell tolerance. Further assessment of their therapeutic potential in this regard is warranted.
Nguyen
Phuong
P
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Geiger
Terrence L
TL
D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D016923:Cell Death; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005822:Genetic Vectors; D006801:Humans; D007108:Immune Tolerance; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D013997:Time Factors; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology; D014161:Transduction, Genetic
D000941:Antigens; D016207:Cytokines; D008070:Lipopolysaccharides; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; C421864:hen egg lysozyme; D009113:Muramidase