Route of Immunization with Peptide-pulsed Dendritic Cells Controls the Distribution of Memory and Effector T Cells in Lymphoid Tissues and Determines the Pattern of Regional Tumor Control

Abstract

We have established that the route of immunization with peptide-pulsed, activated DC leads to memory CD8+ T cells with distinct distributions in lymphoid tissues, which determines the ability to control tumors growing in different body sites. Both intravenous (i.v.) and subcutaneous (s.c.) immunization induced memory T cells in spleen and control of metastatic-like lung tumors. s.c. immunization also induced memory T cells in lymph nodes (LNs), imparting protection against subcutaneously growing tumors. In contrast, i.v. immunization-induced memory was restricted to spleen and failed to impart protective immunity against subcutaneously growing tumors. Memory cell distribution and tumor control were both linked to injection route–dependent localization of DCs in lymphoid compartments. Using peripheral LN–ablated mice, these LNs were shown to be essential for control of subcutaneously growing tumors but not lung metastases; in contrast, using immunized asplenic mice, we found that the spleen is necessary and sufficient for control of lung tumors, but unnecessary for control of subcutaneously growing tumors. These data demonstrate the existence of a previously undescribed population of splenic-resident memory CD8 T cells that are essential for the control of lung metastases. Thus, regional immunity based on memory T cell residence patterns is an important factor in DC-based tumor immunotherapy.

Impaired Protection against Mycobacterium bovis Bacillus Calmette-Guérin Infection in IL-15-Deficient Mice

“…route of BCG administration we used in the present study does not model for mycobacterial infections, which usually enter the body through respiratory tract, or for BCG vaccination in human, which is s.c. delivered. However, there is evidence that CD8 ϩ CTL cells might not be able to migrate to lung efficiently after s.c. vaccination (30). Furthermore, i.p.…”

Dendritic Cell Immunization Route Determines Integrin Expression and Lymphoid and Nonlymphoid Tissue Distribution of CD8 T Cells

“…A ppropriately activated dendritic cells (DC) 4 are potent APC, and exogenously administered Ag-pulsed DC induce specific CD8 ϩ T cell responses against viral and tumor Ags (1)(2)(3)(4). However, the cellular nature and migration properties of exogenous DC limit their distribution in lymphoid compartments in an injection route-dependent manner (3,(5)(6)(7)(8)(9), leading to regionally constrained immune responses (3,5).…”

“…Exogenous DC injected by i.v. or s.c. routes traffic into spleen alone or spleen and draining peripheral LN, respectively (3,(5)(6)(7)(8)(9), and induce primary responses localized to these same compartments (3). Importantly, neither s.c. nor i.v.…”

“…However, the cellular nature and migration properties of exogenous DC limit their distribution in lymphoid compartments in an injection route-dependent manner (3,(5)(6)(7)(8)(9), leading to regionally constrained immune responses (3,5). Thus, in contrast to replicating viral or bacterial immunogens that distribute widely in the body, immunization with bone marrow-derived DC (BMDC) creates the possibility to study the time course and characteristics of the immune response initiated in individual lymph nodes (LN) in exquisite detail.…”

Site-Dependent Recruitment of Inflammatory Cells Determines the Effective Dose of Leishmania major

“…Vaccination by different routes has also been shown to influence the efficacy of vaccines against parasitic, bacterial, and viral infections, as well as cancer (3,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). In the case of infections initiated in the skin by the bite of an insect vector, such as Yersinia, Plasmodium, Borrelia, and Leishmania infections (29), the use of an intradermal route of infection would appear to be critical, since the initial interaction between these pathogens and the host takes place primarily in the skin under natural conditions (11,15,(30)(31)(32).…”