Lymph nodes (LNs) are dynamic organs responsible for providing a supportive and centralized environment for the generation of immune response. Utilizing a highly organized network of non-hematopoietic stromal cells, the LN serves as the context in which the immune system collects and presents antigen, promotes innate and adaptive immune interaction, and generates protective cell-mediated and humoral immunity. In this way, proper organization and function of the LN environment is a critical component of effective immunity, and understanding its complexity has direct impact on the ability to generate and modulate primary immune response to specific antigens. To this end, the LN architecture, underlying stromal networks, and environmental and cellular responses to influenza vaccination were investigated. Using novel approaches to conduit imaging, details of the collagen network that comprises the LN scaffolding have been integrated into current understandings of LN architecture. The cellular compartment responsible for the maintenance of that scaffolding, fibroblastic reticular cells (FRCs), have been studied using an induced diptheria toxin receptor model. By specifically ablating the FRC population in mice, their role in the maintenance of T cell homeostasis has been confirmed in vivo. More surprisingly, a disruption of the FRC network resulted in a loss of B cell follicle structure within LNs, and a reduction in humoral immunity to influenza vaccination. These findings led to the identification of a new subset of FRCs which reside in B cell follicles, and serve as a critical source of the B cell survival factor BAFF. Turning towards the hematopoietic response to influenza vaccination, a highly unexpected lymph node resident dendritic cell (LNDC) response has been identified following vaccine antigen deposition within specialized sites in the LN medulla. Rapid migration of LNDCs into these sites optimizes exposure of the population to viral antigen, and de novo synthesis of a CXCL10 chemokine gradient by activated LNDCs ensures efficient antigen specific \(CD4^+\) T cell response, and protective humoral immunity - independent of migratory dendritic cell status. Altogether, these studies highlight a highly dynamic, responsive LN environment with direct influence on primary immune response - the understanding of which has broad implications in vaccine biology.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/13102331 |
| Date | 22 October 2014 |
| Creators | Woodruff, Matthew Charles |
| Contributors | Carroll, Michael, Turley, Shannon J. |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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