Julie Magarian Blander

Regulation of Antigen Presentation: We were the first to demonstrate TLR control phagosome maturation kinetics, facilitating the delivery of internalized antigens to lysosomes for degradation and subsequent presentation by major histocompatibility complex (MHC) molecules. Our research on cross-presentation by DCs, uncovered unknown intracellular stores of MHC class I and defining the signals controlling their selective recruitment to phagosomes carrying TLR ligands. These findings led to the discovery of noncanonical cross-presentation as a cell autonomous pathway, allowing DCs to overcome viral immune evasion of MHC-I presentation and rescue CD8 T cell priming. Currently, we are leveraging this pathway in designing pancoronavirus vaccines.

Vita-PAMPs in Vaccine Design: Our pioneering work introduced the concept of vita-PAMPs, molecular signatures exclusive to live microorganisms. Identifying bacterial mRNAs and cyclic-di-AMP as vita-PAMPs, we unveiled their role in triggering heightened innate and cellular stress responses in macrophages. Our research explained why live attenuated vaccines outperform their inactivated counterparts. Bacterial mRNA enhances dead vaccine efficacy by promoting follicular T helper cell differentiation and a robust B cell response. Vita-PAMPs hold potential to enhance current vaccines and design novel, safe adjuvants mirroring live vaccine efficacy.

Immune Consequences of Cell Death: We established that host cell apoptosis during infection influences the T helper 17 (TH17) response, linking apoptotic cell antigens to autoimmunity. Our findings challenged the conventional view of passive shedding of dying intestinal epithelial cells, revealing their active sampling by resident phagocytes. These insights into inflammatory pathways and immune suppression mechanisms have implications for understanding and treating Inflammatory Bowel Disease (IBD), emphasizing the importance of mucosal healing.

Innate Immune Barriers Against Malignant Cellular Transformation. Exploring innate immune defenses against early cancer development is a crucial but understudied area. Existing knowledge, mostly derived from established tumors in mice and humans, emphasizes inflammation's tumor-supportive roles and suppressed anti-tumor immunity. The lack of focus on early cancer stages is attributed to limited animal models replicating the transition from premalignancy to malignancy. Human data on immune regulation during pre-malignancy is scarce as patients typically seek medical attention when malignancy is established. Our lab is pioneering a new research direction by creating mouse models to investigate innate immune barriers in the premalignant phase.

Innate Immunity for Cancer Immunotherapy: In cancer immunotherapy, our lab devised a tumor cell vaccination strategy leveraging bacterial flagellin to simultaneously activate TLR and NLR pathways. This dual targeting induced potent anti-tumor CD4 and CD8 T cell responses, protecting mice against tumor challenges. In ongoing work, we identified novel inflammasome agonists that elicit potent adjuvant and anti-tumor activity, and are optimizing delivery methods for preclinical cancer vaccines and tumor microenvironment modulation.

Current Projects:

• The regulation of antigen cross-presentation by innate sensors
• Innate sensing of vita-PAMPs, signatures of microbial life
• Innate sensing and immune consequences of cell death
• Innate immunosurveillance against cancer