Plasticity of Ly-6C Myeloid Cells in T Cell Regulation

CD11b + Ly-6C hi cells, including inflammatory monocytes (IMCs) and inflammatory dendritic cells (IDCs), are important in infectious , autoimmune, and tumor models. However, their role in T cell regulation is controversial. In this article, we show that T cell regulation by IMCs and IDCs is determined by their activation state and is plastic during an immune response. Non-activated IMCs and IDCs function as APCs, but activated IMCs and IDCs suppress T cells through NO production. Suppressive IMCs are induced by IFN-g, GM-CSF, TNF-a, and CD154 derived from activated T cells during their interaction. In experimental autoimmune encephalomyelitis, CD11b + Ly-6C hi cells in the CNS are increasingly activated from disease onset to peak and switch their function from Ag presentation to T cell suppression. Furthermore, transfer of activated IMCs or IDCs enhances T cell apoptosis in the CNS and suppresses experimental autoimmune encephalomyelitis. These data highlight the interplay between innate and adaptive immunity: immunization leads to the expansion of Ly-6C hi myeloid cells initially promoting T cell function. As T cells become highly activated in the target tissue, they induce activation and NO production in Ly-6C hi myeloid cells, which in turn suppress T cells and lead to the contraction of local immune response. M ononuclear leukocytes, including monocytes, macro-phages, and dendritic cells, play essential roles in shaping the T cell response (1, 2). They sense danger signals, capture and present Ags, program T cell activation and differentiation, and also participate in the immune effector functions. In contrast, because of their close interaction with T cells and the ability to migrate into inflammatory tissues, there has been increased interest in studying the mechanisms by which mono-nuclear leukocytes regulate autoimmune T cells (3–6). Blood monocytes can be classified into two distinct populations: CD11b + Ly-6C 2 CX3CR1 hi resident monocytes and CD11b + Ly-6C hi CCR2 + inflammatory monocytes (IMCs) (7). During an active immune response, IMCs emigrate from the bone marrow in response to MCP-1 and MCP-3 (8, 9), migrate through the blood to inflamed tissues, and then differentiate into macrophages and CD11c + inflammatory dendritic cells (IDCs) (7, 10, 11). In Toxoplasma gondii, Listeria, and Leshimania infection models, IMCs and IDCs play critical roles in microbial clearance (12–15). In addition to their innate effector function, adoptive transfer of ex vivo-purified IMCs enhances CD8 + T cell response in vivo (7, 16). IDCs isolated from Leshimania-infected mice also promoted …