RESUMEN
Ig-like transcript 3 (ILT3) is an inhibitory receptor expressed by tolerogenic dendritic cells. When human CD8(+) T cells are allostimulated in the presence of recombinant ILT3-Fc protein, they differentiate into antigenic specific T suppressor (Ts) cells that inhibit CD4 and CD8 T cell effector function both in vitro and in vivo. ILT3-Fc-induced CD8(+) Ts cells express high amounts of BCL6 that are crucial to their function. Knockdown of BCL6 from unprimed human T cells prevents their differentiation into Ts cells, whereas ex vivo overexpression of BCL6 converts CD8(+) T cells into Ts cells. NOD/SCID mice transplanted with human pancreatic islets and humanized by injection of human PBMCs tolerate the graft and develop BCL6(high) CD8(+) Ts cells when treated with ILT3-Fc before or after the onset of rejection. This indicates that ILT3-Fc acts through BCL6 and is a potent immunosuppressive agent for reversing the onset of allo- or possibly autoimmune attacks against pancreatic islets.
Asunto(s)
Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Proteínas de Unión al ADN/inmunología , Receptores de Superficie Celular/inmunología , Tolerancia al Trasplante/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Femenino , Técnicas de Silenciamiento del Gen , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunohistoquímica , Trasplante de Islotes Pancreáticos/inmunología , Glicoproteínas de Membrana , Ratones , Ratones Endogámicos NOD , Ratones SCID , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores Inmunológicos , Proteínas Recombinantes de Fusión/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
Gene profile analysis of ILT3-Fc-induced Ts revealed a significant upregulation of Zink finger proteins, most of which act as transcriptional repressors. Included among these repressors is BCL6, which was shown to play a critical role in the differentiation of ILT3-Fc-induced T suppressor (Ts) cells. Genes implicated in cell cycle progression were downregulated. Genes encoding numerous inflammatory cytokines and chemokines were also downregulated. In contrast, antiapoptotic genes, as well as members of the WNT and transforming growth factor-ß pathways, were upregulated. This study elucidates certain important aspects of Ts differentiation and function.