SummaryInterleukin 10 (IL-10) and viral Ibl0 (v-IL-10) strongly reduced antigen-specific proliferation of human T cells and CD4 + T cell clones when monocytes were used as antigen-presenting cells. In contrast, IL-10 and v-Ibl0 did not affect the proliferative responses to antigens presented by autologous Epstein-Barr virus-lymphoblastoid cell line (EBV-LCL). Inhibition of antigen-specific T cell responses was associated with downregulation of constitutive, as well as interferon 3'-or Ib4-induced, class II MHC expression on monocytes by IL-10 and v-Ibl0, resulting in the reduction in antigen-presenting capacity of these ceUs. In contrast, IL-10 and v-Ibl0 had no effect on class II major histocompatibility complex (MHC) expression on EBV-LCL. The reduced antigenpresenting capacity of monocytes correlated with a decreased capacity to mobilize intracellular Ca 2 + in the responder T cell clones. The diminished antigen-presenting capacities of monocytes were not due to inhibitory effects of II.-10 and v-Ibl0 on antigen processing, since the proliferative T cell responses to antigenic peptides, which did not require processing, were equaUy well inhibited. Furthermore, the inhibitory effects of Ibl0 and v-IL-10 on antigen-specific proliferative T cell responses could not be neutralized by exogenous Ib2 or Ib4. Although IL-10 and v-IL-10 suppressed IL-lc~, IL-1B, tumor necrosis factor ot (TNF-c~), and IL-6 production by monocytes, it was excluded that these cytokines played a role in antigen-specific T cell proliferation, since normal antigenspecific responses were observed in the presence of neutralizing anti-Ibl, -IL-6, and -TNF-tx mAbs. Furthermore, addition of saturating concentrations of IL-lot, IL-I~, IL-6, and TNF-o~ to the cultures had no effect on the reduced proliferative T cell responses in the presence of Ibl0, or v-Ibl0. Collectively, our data indicate that IL-10 and v-IL-10 can completely prevent antigen-specific T cell proliferation by inhibition of the antigen-presenting capacity of monocytes through downregulation of class II MHC antigens on monocytes.