Establishment of Early Lymphoid Organ Infrastructure in Transplanted Tumors Mediated by Local Production of Lymphotoxin α and in the Combined Absence of Functional B and T Cells

Abstract

Lymphoid organogenesis is a highly coordinated process involving orchestrated expression of a number of genes. Although the essential role of lymphotoxin α (LTα) for the normal development of secondary lymphoid organs is well established, it is not clear to which extent it depends upon cooperation with T and B lymphocytes for lymphoid neo-organogenesis. To determine whether LTα is sufficient to mediate recruitment of basic elements needed for lymphoid organogenesis, we made use of a LTα-transfected cell line as an experimental tool and established tumors in nude and SCID mice. Our data showed that high endothelial venules formed and follicular dendritic cells accumulated and differentiated in response to LTα in the absence of lymphocytes. A CD4+CD3−CD11c+ cell population that is found in the secondary lymphoid organ was also recruited into tumors expressing LTα. Furthermore, in nude mice, B cells migrated in response to LTα and formed intratumoral follicles. These B cell follicles were structurally well equipped with follicular dendritic cell networks and high endothelial venules; however, they were not functionally active; e.g., those B cells specific for a surrogate Ag expressed by the tumor were found in the spleen, but not in the tumor. We show that, even in the absence of functional T and B lymphocytes, local expression of LTα in transplanted tumors induced typical stromal characteristics of lymphoid tissue, emphasizing that LTα is a critically important cytokine for formation of lymphoid organ infrastructure.