| Dendritic cells (DC) are potent antigen presenting cells in the immune system and stimulate robust CD8+ T cell responses in vivo. DC are currently being used as immunogens for cancer vaccines, despite limited knowledge about the localization and phenotype of T cell responses that exogenous DC stimulate in vivo. In the present work, we have developed a murine model system to characterize CD8+ T cell responses that develop within specific lymphoid compartments after bone marrow-derived DC (BMDC) immunization, and track this response with great precision over time and space. Mesenteric LN and spleen were differentially targeted by intraperitoneal (i.p.) and intravenous (i.v.) administration of BMDC respectively, whereas mediastinal LN were targeted by both routes. BMDC injected by either route activated T cells to upregulate alpha4beta1 integrin, but the kinetics of upregulation was lymphoid compartment-dependent. Only T cells activated in mesenteric LN after i.p. immunization expressed high levels of alpha4beta7, and only i.p. immunization generated gut-localized effector T cells. Surprisingly, these alpha4beta7hi cells also redistributed to mediastinal LN via alpha4beta7 binding to a ligand other than MAdCAM-1 by 3 days after immunization. These results demonstrate the importance of lymphoid compartment in determining integrin expression on activated T cells. While T cells in all priming compartments after i.v. and i.p. immunization divided up to 7 times within 72hr of BMDC injection, a surprisingly high fraction retained expression of CD62L. These cells were also found in non-contiguous lymph nodes at this time. This was not due to delayed migration of BMDC, but to T cell redistribution via a CD62L-dependent mechanism. These extensively divided CD62Lhi T cells acquired other memory cell markers within 7 days, and persisted in both the priming and non-contiguous LN for at least 40 days. Thus, a subset of T cells that gives rise to central memory cells can be identified as early as 72hr after DC immunization based on CD62L retention and redistribution to non-contiguous LN. These advances in understanding the relationship between route of immunization, homing capacities of activated T cells, and the development of memory will enable the design of more effective DC-based cancer vaccines. |
