Regulation of T Effector Cell Function by Exogenous Gangliosides (Paperback)

A major barrier to the development of effective tumor immunotherapy is the ability of tumors to create an immunosuppressive microenvironment that inhibits the development of effective T cell mediated anti-tumor responses. Although several mechanisms are known to be involved in inhibiting tumor specific immunity, the initiating factors that promote the development of an immunosuppressive microenvironment during tumor pathogenesis are not well understood. It has been previously demonstrated that tumor shed gangliosides have immunomodulatory properties, suggesting that these inhibitory factors may play a role in initiating an immunosuppressive microenvironment. In the current studies we have focused on the role of ganglioside exposure on antigen presenting cells (APCs) and on subsequent development of T cell effector responses. To better define the immunomodulatory properties of gangliosides on antigen-specific T cell activation and development we have utilized a well-characterized in vitro model system where ganglioside-treated murine bone marrow derived dendritic cells were used to prime and activate antigen specific CD4+ AND TCR transgenic cells. Using this model system, we have shown that ganglioside treatment inhibits LPS-induced co-stimulatory molecules CD80 and CD86 up-regulation and cytokine production by bone marrow DCs. Furthermore, when ganglioside pre-treated bone marrow DCs were used as APCs to prime and activate naive CD4+ T cells, they induced a defect in Th effector cell development. This defect was associated with the development of a subset of suppressive cells that could inhibit Th1 effector responses by previously activated effector T cells in a cell-contact and dose dependent manner. Although the precise nature and suppressive mechanisms mediated by this subset of suppressive cells remains to be elucidated, our data suggest that these are not the typical FoxP3 expressing cells. In total our findings suggest that tumor shed gangliosides may contribute to the initiation of a tumor immunosuppressive microenvironment by inducing the development of a suppressive cell population that subvert tumor-specific T cell responses in a cell-contact dependent manner.