CONTRASTING EFFECTS OF TGF-BETA-1 AND TNF-ALPHA ON THE DEVELOPMENT OFDENDRITIC CELLS FROM PROGENITORS IN MOUSE BONE-MARROW

Dendritic cells (DC) are a distinct population of leukocytes and speci alized antigen-presenting cells for T cell responses, Prior work has s hown that GM-CSF can induce the development of large numbers of DC fro m proliferating progenitors in mouse hone marrow. We have monitored th e effects of potentially enhancing and suppressive cytokines in these cultures, In this system, many immature DC develop from proliferating precursors during the first six days of culture, and between days 6-8 maturation of typical nonadherent and nonreplicating DC takes place, T he maturation is accompanied by a large increase in the expression of major histocompatibilities complex class II (MHC II) and B7-2/CD86, an d in mixed leukocyte reaction stimulating activity, Tumor necrosis fac tor-alpha (TNF-alpha), previously shown to be required for development of human DC, was found to enhance the maturation of mouse DC in the l ast two days of culture. Transforming growth factor-beta 1(TGF-beta 1) , on the other hand, almost totally blocked DC maturation, but it had to be given in the first six days of culture when the DC were actively proliferating. TGF-beta 1 did not block the production of immature, M HC II-positive but B7-2/CD86-negative DC. Maturation would take place between days 6-8 as long as the cultures were depleted of Fc-receptor- bearing cells, or if TNF-alpha were added. In both instances, maturati on was not blocked even when TGF-beta 1 remained in the culture, We co nclude that the development of DC, in response to GM-CSF, can be modif ied by other cytokines, TGF-beta 1 is suppressive but only indirectly via Fc-receptor-bearing suppressive cells, presumably suppressive macr ophages, while TNF-alpha enhances the final maturation of DC.