The immune system must maintain a delicate balance between activation and tolerance. It is required to quickly respond and eliminate a variety of threats while at the same time remain unresponsive upon encountering normal self-cells or commensal bacteria. We have created a system to track antigen trafficking throughout the immune system and using this system have identified a pathway of antigen flow from peripheral tissues and tumors to the draining lymph node (LN). By tracking antigen from steady-state tissues and tumors, we find that antigen is handled differentially in the LN depending on the inflammatory context in the periphery. During pronounced inflammation, self-antigen shows altered trafficking consistent with that of tumor antigen. Interestingly, using both gut and skin systems, commensal bacteria-derived antigen displayed the unique quality of cell type specific uptake. While each of the various migratory dendritic cell (DC) types were proficient at uptake of self and tumor antigens, only migratory CD11b+ DC and macrophages showed detectable commensal antigen uptake. Additionally, tracking of commensal bacteria-derived antigen within DC showed minimal antigen trafficking to the LN, suggesting different modes of maintaining immune tolerance are at play depending on the antigen source. We find that self-antigen can drain to the LN via migratory DC but is limited from passing to resident DC populations, which appears to prevent robust self-reactive T-cell priming. However, in the case of commensal antigen, the restriction of antigen flow is early in the pathway, thus effectively keeping the LN ignorant of antigen. Identifying the signals that restrict antigen flow in cases of immune tolerance will likely provide insight into how tumor antigen availability affects immune activation. Understanding how self, commensal and tumor antigens are handled by immune cells under various contexts will help inform the development of new targeted immunotherapies that seek to activate or inhibit immune activation in cases of cancer and autoimmunity.

Citation Format: Megan K. Ruhland, Edward W. Roberts, Matthew F. Krummel. Modulating antigen flow to control immune tolerance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B184.