Vaccinations that are based on the use of live, attenuated infectious agents (ie. Vaccinia virus, MMR) can produce immune memory lasting for many decades without any need for boosting. These live attenuated vaccinations generate both humoral and cellular immune memory, accounting for much of the increased duration of protective immune memory. In addition, it is well documented that antigen derived from infectious agents persists for an extended period of time after the infection is cleared from the host. This persistence of antigen has been shown to help maintain different functional pools of antigen specific memory cells which display varying efficiencies in the clearance of an infectious challenge. While stromal cells other than FDCs have been implicated in the capture and maintenance of persisting antigen, the identity of these cells, their location within the secondary lymphoid tissue, and the underlying mechanisms determining how antigen persists in/on these cells, have never been clearly demonstrated. We have published extensively on the nature of vaccine adjuvants and their capacity to elicit robust cellular immunity. We can now show that this subunit-based vaccine approach, similar to viral challenge, results in long term persistence of antigen in the host. Surprisingly, we found that the persisting antigen is maintained not within the FDC and/or the fibroblastic reticular cell (FRC) network, but rather captured and held on or within the LECs. The coupling of LEC proliferation and antigen capture identifies a previously unappreciated mechanism by which the stroma in secondary lymphoid tissue maintains antigens against which a robust response has been initiated, in effect archiving these antigens for periods of time lasting well after the peak of normal immune response. Our results are the only report to identify the central role of LECs in antigen capture and archiving. With these data and questions in mind, we hypothesize that proliferation of LECs in response to cues derived from local inflammatory conditions and T cell expansion induces their expression of molecules necessary for antigen capture. We further hypothesize that specific subsets of DCs can acquire this LEC-archived antigen from within the subcapsular region of the lymph node and present the antigen to circulating antigen specific memory T cells, thereby increasing memory T cell recruitment to the tissue, increasing T cell self-renewal, enhancing T cell effector function, or some combination of all of the above. These hypotheses ultimately predict that the elimination of persisting antigen will negatively affect the speed and/or magnitude of the memory T cell response to infectious challenge. Because our preliminary data show critical roles for T cells, DCs, and LECs in the process of antigen capture and archiving after vaccination or viral challenge, we will test our stated hypotheses with specific aims focusing on the role of each cell type in this process.
Vaccinations that are based on the use of live, attenuated infectious agents (i.e. Vaccinia virus, MMR) can produce immune memory lasting for many decades without any need for boosting. These live attenuated vaccinations generate both humoral and cellular immune memory, accounting for much of the increased duration of protective immune memory. In addition, it is well documented that antigen derived from infectious agents persists for an extended period of time after the infection is cleared from the host. This persistence of antigen has been postulated, and in some cases shown, to help maintain different functional pools of antigen specific memory cells which display varying efficiencies in the clearance of a secondary infectious challenge. We have published extensively on the nature of vaccine adjuvants and their capacity to elicit robust cellular immunity. In the process, we recently observed that both subunit-based vaccination and viral challenge can result in long term persistence of antigen in the host and that this antigen resides on a stromal cell type, lymphatic endothelial cells (LECs), not previously associated with long term antigen persistence. This project will elucidate the mechanisms by which protein antigen persists on the LECs following viral challenge or subunit vaccination, examine the process by which this antigen is manipulated by both hematopoetic and non-hematopoetic cells, and determine the immunologic impact of that antigen persistence on the development and maintenance of protective immunity against infectious agents.
