Kevin Telfer

Program: Immunology

Current advisor: Gwendalyn J Randolph, PhD

Undergraduate university: Case Western Reserve University, 2022

Enrollment year: 2022

Research summary
My work seeks to define how HDL cholesterol efflux maintains the function of highly phagocytic lymph node macrophages and test whether they supply lymph borne antigens to lymph node resident dendritic cells.

High-density lipoproteins (HDL) perform the essential function of removing excess insoluble cholesterol from cells. The process is so important that abnormal HDL levels were recently linked to all-cause mortality including for non-cardiovascular diseases such as cancer and to the severity of infectious disease. Humans lacking the two cholesterol transporters that facilitate cholesterol efflux to HDL, ABCA1 and ABCG1, present with lipid-laden lymphoid tissues without developing premature cardiovascular disease. Our preliminary data shows that specific deletion of these transporters in the macrophages causes mice to develop profound lipid accumulation in the medullary sinus of the lymph node even on a diet without excess cholesterol. Furthermore, fluorescently tagged HDL developed in the Randolph laboratory is enriched in the medullary sinus and binds to macrophages there. These medullary sinus macrophages (MSMs) are known to filter large proteins and particulate from lymph which may require enhanced cholesterol handling but also provide MSMs with a complete survey of antigens in lymph.
Current dogma states that antigen is acquired and presented by migratory dendritic cells (DCs) or can be directly captured by resident DCs if it is small enough to enter the T cell zone of the lymph node (LN). However, some studies support the idea of an alternative route since migratory DCs are not required to elicit a CD8 T cell response against bacterial sized particles. While studies support that LN-resident cDC1s are a major cross presenting subset, it’s unclear how these resident DCs could acquire antigens that are too large to enter the T cell zone. We propose that MSMs capture particulate antigens and transfer them to LN-resident DCs but rely on HDL-mediated cholesterol efflux to clear accumulating cholesterol. Previous work showed that macrophages in the spleen directly transfer antigen to DCs and that LN macrophages are required for developing a tumor-protective CD8 T cell response against dead cell-associated antigens independent of migratory DCs. My project seeks to test whether MSMs transfer large model antigens to resident DCs in the lymph node using novel genetic approaches to delete MSMs and imaging approaches to capture the interactions between MSMs and DCs. It will also define interactions between LN macrophages and HDL for the first time using a novel fluorescently tagged HDL and asses the contribution of dead cell cholesterol to MSMs. MSMs in tumor-draining LNs have an elevated signature of lipid handling, thus the proposed study will test if mice with cholesterol efflux-impaired macrophages are unable to effectively form a cytotoxic T cell response against an immunogenic tumor.

Graduate publications
Lee DD, Telfer KA, Davis DL, Smyth LCD, Ravindran R, Czepielewski RS, Huckstep CG, Du S, Kurashima K, Jain AK, Kipnis J, Zinselmeyer BH, Randolph GJ. 2025 ADAPT-3D:accelerated deep adaptable processing of tissue for 3-dimensional fluorescence tissue imaging for research and clinical settings. Sci Rep, 15(1):31841. PMCID: PMC12397274