TARGETED EXPRESSION OF MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS-II MOLECULES DEMONSTRATES THAT DENDRITIC CELLS CAN INDUCE NEGATIVE BUT NOT POSITIVE SELECTION OF THYMOCYTES IN-VIVO

It is well established that lymphoid dendritic cells (DC) play an impo rtant role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major h istocompatibility complex (MHC) class II+ ''interdigitating cells'' in the thymus during thymocyte development. Thymic DC have been implicat ed in tolerance induction and also by some authors in inducing major h istocompatibility complex restriction of thymocytes. Most of our knowl edge about thymic DC was obtained using highly invasive and manipulato ry experimental protocols such as thymus reaggregation cultures, suspe nsion cultures, thymus grafting, and bone marrow reconstitution experi ments. The DC used in those studies had to go through extensive isolat ion procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been repo rted to be not identical to those of DC in vivo, we intended to establ ish a system that would allow us to investigate DC function avoiding a rtificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. U sing the CD11c promoter we expressed MHC class II I-E molecules specif ically on DC of all tissues, but not on other cell types. We report th at I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4(+) T cells, and to a less complete extent, CD8(+) T cells . In contrast, if only DC expressed I-E in a class II-deficient backgr ound, positive selection of CD4(+) T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.