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In the early stages of viral infection, outcomes depend on a race between expansion of infection and the immune response generated to contain it. We combined in situ tetramer staining with in situ hybridization to visualize, map, and quantify relationships between immune effector cells and their targets in tissues. In simian immunodeficiency virus infections in macaques and lymphocytic choriomeningitis virus infections in mice, the magnitude and timing of the establishment of an excess of effector ceils versus targets were found to correlate with the extent of control and the infection outcome (i.e., control and clearance versus partial or poor control and persistent infection). This method highlights the importance of the location, timing, and magnitude of the immune response needed for a vaccine to be effective against agents of persistent infection, such as HIV-1.

In the early stages of viral infection, outcomes depend on a race between expansion of infection and the immune response generated to contain it. We combined in situ tetramer staining with in situ hybridization to visualize, map, and quantify relationships between immune effector cells and their targets in tissues. In simian immunodeficiency virus infections in macaques and lymphocytic choriomeningitis virus infections in mice, the magnitude and timing of the establishment of ah excess of effector cells versus targets were found to correlate with the extent of control and the infection outcome (i.e., control and clearance versus partial or poor control and persistent infection). This method highlights the importance of the location, timing, and magnitude of the immune response needed for a vaccine to be effective against agents of persistent infection, such as HIV-1. [ABSTRACT FROM AUTHOR]

Peripheral tolerance to shared Ags expressed on both tumors and normal self-tissues presents a major barrier to T cell-based immunotherapy as a treatment for cancer. To assess the activity of tumor-specific T cells against spontaneously arising carcinomas in the context of shared Ag expression, we developed a model system whereby an identified tumor Ag, tumor ERK (tERK), is expressed transgenically on both normal mammary tissue and spontaneous mammary carcinomas. Transfer of in vitro-activated, tERK-specific DUC18 T cells delayed spontaneous tumor development in tERK-expressing mice when T cells were given before the development of palpable carcinomas. However, antitumor activity mediated by in vitro-activated DUC18 T cells, as measured by responsiveness against a transplanted tERK-expressing fibrosarcoma challenge, was lost within days of transfer. This loss was due to expression of tERK as a self-Ag on normal tissues and was independent of the presence of mammary tumors. In contrast, transferred naive DUC18 T cells maintained a long-term protective function in tERK-expressing mice. Ten-fold fewer naive T cells activated in vivo were able to replicate the delay in spontaneous tumor development achieved by in vitro-activated T cells. These results are in contrast to our earlier studies using transplanted tumors alone, in which in vitro-activated DUC18 T cells were more efficacious than naive DUC18 T cells and highlight the need to perform tumor studies in the presence of tumor Ag expression on normal self-tissue.

The lung is a common site of metastatic and primary tumor growth, and has been shown to be an immunosuppressive environment. We tested the impact of the lung environment on the development of tumor-specific T cell responses against the CMS5 fibrosarcoma, and found a deficit in the efficacy of naive tumor-specific DUC18 T cells against tumors established in the lung. One hundred-fold more naive tumor-specific T cells were required to protect against tumor development or reject established tumors in the lung than an identical tumor challenge delivered s.c. in the flank. Importantly, CMS5 growing in the flank facilitated the rejection of tumors present in the lungs. In the presence of flank tumors, transferred T cells were not phenotypically altered but were present in much greater numbers in the parabronchial lymph nodes, bronchoalveolar lavage, and lung parenchyma than in mice bearing lung tumors alone. We hypothesized that APC present in the lung and skin draining lymph nodes were differentially initiating T cell proliferation, leading to differences in the size of the final effector populations. A direct comparison of DUC18 T cell proliferation against APC from flank or lung draining lymph nodes showed profoundly greater proliferation to flank draining lymph node APC. The impaired stimulation of naive T cell proliferation by lung draining APC provides one mechanistic explanation for the lower overall immune response, and inability to effectively reject tumors, in the lung.