Our preliminary data suggests that antigen uptake is dependent on the expansion of LECs. If expansion of the lymph node leads to antigen archiving, does contraction of the lymph node lead to antigen hand-off? There appear to be two mechanisms of antigen hand-off/exchange from LECs to hematopoietically derived APCs. First, contraction of the lymph node results in LEC apoptosis as the lymph node decreases in size. Presumably some of the LECs that apoptose are holding onto antigen. Thus, archived antigen is given to dendritic cells or other antigen presenting cells through the uptake of apoptotic LECs. A second mechanism of antigen exchange occurs after the lymph node has returned to normal size. We will address mechanisms of steady state antigen exchange for which we have preliminary data. We will first evaluate if antigen exchange in the steady state is complement mediated and second evaluate if antigen exchange in the steady state is exosome mediated. Our last aim will test how multiple rounds of expansion and contraction affects antigen archiving and antigen exchange. The extent with which antigen is archived, i.e. which LECs archive antigen, how it is retained during lymph node expansion and contraction, and how it is retained and acquired after multiple rounds of infection is the focus of this aim. Our overarching hypothesis is that expansion and contraction of the lymph node changes the library of antigens that LECs acquire during infections or immunizations by exchanging antigen with hematopoietically derived APCs. The resulting changes in antigen retention on LECs as a result of antigen exchange likely leads to differences in susceptibility to re-infection and prolonged immunity.
We, and others, have described antigen persistence following a wide variety of viral infections and now immunization. The impact of antigen being retained or archived within the lymph node for extended periods of time appears to be beneficial. However, mechanisms behind how stromal cells exchange antigen to antigen presenting cells during contraction of the lymph node has yet to be understood and thus there is a gap in our understanding of the immune response following viral infection and immunization.
|Lucas, Erin D; Finlon, Jeffrey M; Burchill, Matthew A et al. (2018) Type 1 IFN and PD-L1 Coordinate Lymphatic Endothelial Cell Expansion and Contraction during an Inflammatory Immune Response. J Immunol 201:1735-1747|
|Kedl, Ross M; Lindsay, Robin S; Finlon, Jeffrey M et al. (2017) Migratory dendritic cells acquire and present lymphatic endothelial cell-archived antigens during lymph node contraction. Nat Commun 8:2034|