| Lymphotoxin alpha (LTalpha) and the lymphotoxin alphabeta complex (LTalphabeta) are crucial mediators of lymphoid organogenesis and inflammation, two processes once considered to be distinct both mechanistically and functionally. However, knockout and transgenic studies have revealed a common role for these cytokines in these processes, in part, through regulation of endothelial addressins and lymphoid chemokines. Interestingly, chronic inflammatory lesions in numerous autoimmune and infectious diseases morphologically resemble lymph nodes (LN) with T and B cell compartments, lymphoid chemokine expression, follicular dendritic cell (FDC) networks and high endothelial venules (HEV). These structures, known as tertiary lymphoid organs (TLOs), develop by a process termed "lymphoid neogenesis". Though the mechanisms underlying the development and function of LNs are partially understood, regulation of TLO development and function remains even less clear. This dissertation aims to (1) elucidate the molecular mechanisms used by LTalphabeta to regulate HEV gene expression in LNs and TLOs, (2) evaluate the contribution of the alternative NF-kappaB pathway to lymphoid organogenesis and HEV development (3) determine if TLOs are immunologically functional and (4) investigate the lymphoid chemokine homing requirements involved in TLO development. From these experiments we first demonstrate that LTalphabeta and the alternative NF-kappaB pathway regulate PNAd expression on HEV through induction of HEC-6ST and GlyCAM-1 and provide evidence that this could occur through direct signaling in LTbetaR + HEV. Second, we demonstrate that TLOs contain two important constituents for the induction of immune responsiveness---lymphatic vessels and functional antigen presenting cells that can induce T cell activation in vitro and in vivo. Lastly, we find that the CXCL13:CXCR5 lymphoid chemokine system is differentially required for LN and TLO development. Overall, the studies further elucidate the differential signaling and homing requirements involved in LN and TLO development and implicate LTalphabeta signaling via the alternative NF-kappaB pathway as a central event for the initiation, maturation and function of tertiary lymphoid tissue. |
