Killing of dendritic cells by activated T cells can limit immune responses: Relevance for immunotherapy

Dendritic cells are specialized antigen presenting cells which play a central role in induction of immunity and tolerance. They have the special ability to take up, process and present foreign antigens and thus are potent stimulators for naive T cells. Stimulated T cells start to proliferate and induce immune responses against pathogens, in that they activate macrophages, stimulate B cells to produce antibodies and cytotoxic T cells to kill infected cells in the tissue. Little is known about interactions of tissue dendritic cells, like epidermal Langerhans cells and T cells in the peripheral tissues. During inflammation Langerhans cells migrate from the skin into the draining lymph nodes where they activate T cells. The resulting effector T cells migrate back to the inflamed sites and help to eliminate infected cells. However, this killing potential can also be misguided so that dendritic cells themselves become targets and are killed by the activated T cells. This may occur both in the skin and in the lymph nodes. Since dendritic cells efficiently present antigenic peptides in their MHC molecules they are indeed optimal targets for cytotoxic T cells. This clearance of dendritic cells might be a physiological mechanism to limit ongoing immune responses. However, the mechanisms and the extent of cytotoxicity towards dendritic cells is still unknown. The elucidation of these questions is important for the use of dendritic cells in the immunotherapy of a wide range of tumors, as is presently being performed in several clinical trials. Patient-derived dendritic cells are loaded with tumor antigens and are injected repeatedly into the patients during the treatment cycles. Results so far are promising, however, the immune responses observed decline with prolonged therapy. There are several reasons for this decline: Migration of dendritic cells to lymphatic tissue after intracutaneous injections is not very efficient and the immuno-compromised state of the patients could impair the outcome of the anti-tumor response. However, the killing of tumor-peptide loaded dendritic cells by activated T cells could be another important reason for the lack of persistent success especially when intervals between injections are short. Therefore, the specific goal of this study is to investigate interactions between antigen-loaded dendritic cells and antigen-specific effector T cells in peripheral (skin), lymphatic (lymph nodes) and tumor (melanoma) tissues. Specifically, I wish to address the question of whether and how dendritic cells are killed by activated T cells in vivo and whether this could impair the outcome of dendritic cell-based immunotherapy.