Uneven Distribution of MHC Class II Epitopes within the Influenza Virus

The identification of T cell epitopes is crucial for the understanding of the host immune response during infection. While much is known about the MHC class I-restricted response following influenza virus infection of C57BL/6 mice, with over 16 CD8 epitopes identified to date, less is known about the MHC class II-restricted response. Currently, only a few I-Ab-restricted T helper epitopes have been identified. Therefore, several important questions remain about how many class II epitopes exist in this system and whether these epitopes are evenly distributed within the most abundant viral proteins. In order to address these questions, we analyzed the repertoire of epitopes that drive the CD4b T cell response to influenza virus infection in C57BL/6 (H-2b) mice. Using a panel of overlapping peptides from each of the viral proteins we show that approximately 20–30 epitopes drive the CD4 T cell response and that the majority of these peptides are derived from the NP and HA proteins. We were also able to demonstrate that vaccination with one of the newly identified epitopes, HA211–225/Ab, resulted in increased epitope-specific T cell numbers and a significant reduction in viral titers following influenza virus challenge

Differential Antigen Presentation Regulates the Changing Patterns of CD8+ T Cell Immunodominance in Primary and Secondary Influenza Virus Infections

The specificity of CD8+ T cell responses can vary dramatically between primary and secondary infections. For example, NP366–374/Db- and PA224–233/Db-specific CD8+ T cells respond in approximately equal numbers to a primary influenza virus infection in C57BL/6 mice, whereas NP366–374/Db-specific CD8+ T cells dominate the secondary response. To investigate the mechanisms underlying this changing pattern of immunodominance, we analyzed the role of antigen presentation in regulating the specificity of the T cell response. The data show that both dendritic and nondendritic cells are able to present the NP366–374/Db epitope, whereas only dendritic cells effectively present the PA224–233/Db epitope after influenza virus infection, both in vitro and in vivo. This difference in epitope expression favored the activation and expansion of NP366–374/Db-specific CD8+ memory T cells during secondary infection. The data also show that the immune response to influenza virus infection may involve T cells specific for epitopes, such as PA224–233/Db, that are poorly expressed at the site of infection. In this regard, vaccination with the PA224–233 peptide actually had a detrimental effect on the clearance of a subsequent influenza virus infection. Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies

Uneven Distribution of MHC Class II Epitopes within the Influenza Virus

The identification of T cell epitopes is crucial for the understanding of the host immune response during infection. While much is known about the MHC class I-restricted response following influenza virus infection of C57BL/6 mice, with over 16 CD8 epitopes identified to date, less is known about the MHC class II-restricted response. Currently, only a few I-Ab-restricted T helper epitopes have been identified. Therefore, several important questions remain about how many class II epitopes exist in this system and whether these epitopes are evenly distributed within the most abundant viral proteins. In order to address these questions, we analyzed the repertoire of epitopes that drive the CD4b T cell response to influenza virus infection in C57BL/6 (H-2b) mice. Using a panel of overlapping peptides from each of the viral proteins we show that approximately 20–30 epitopes drive the CD4 T cell response and that the majority of these peptides are derived from the NP and HA proteins. We were also able to demonstrate that vaccination with one of the newly identified epitopes, HA211–225/Ab, resulted in increased epitope-specific T cell numbers and a significant reduction in viral titers following influenza virus challenge

Tumor macroenvironment and metabolism

In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%–20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient’s outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described

Reovirus 1/L as a Model to Study the Induction of Optimal Immunity at Mucosal and Systemic Sites

Achieving protective immunity at mucosal sites is critically important for effective immunization against pathogens that colonize the host via the wet epithelium. We utilized reovirus 1/L infection of mice to study immunization strategies for the induction of optimal humoral and cell-mediated immunity at mucosal surfaces. The humoral and cell-mediated responses at mucosal and systemic sites were monitored following upper respiratory tract, or systemic inoculation. Utilizing these models, we found that the combined upper and lower respiratory tract inoculation resulted in optimal humoral immunity proximally (in the respiratory tract), distrally (in the oral, gastrointestinal, and urogenital tracts), and systematically. This immune response induces neutralizing antibodies and could be boosted following secondary inoculation. In addition to these findings, we also demonstrated that combined upper and lower respiratory tract inoculation resulted in optimal cell-mediated responses in the gastrointestinal tract and systematically. Using a novel reovirus-specific bromodeoxyuridine incorporation assay, we found that the following combined upper and lower respiratory tract inoculation there was increased proliferation of CD4 and CD8 (helper and cytotoxic) T-lymphocytes in the spleen and draining lymph nodes. Taken together this data indicated that combined upper and lower respiratory tract inoculation induces optimal humoral and cell-mediated immunity. Finally, we monitored the proliferative responses to individual reovirus gene segments following systemic or upper and lower respiratory tract inoculation. Using this system we found that the response in systemic tissues was directed at reovirus outer capsid protein regardless of the route of inoculation. In contrast, after mucosal inoculation the response in the draining lymph nodes was directed at an inner capsid protein. Therefore these results suggest that differential antigen processing and/or presentation occurs at musical vs. systemic sites. This data has important clinical implications for vaccine delivery since induction of the upper and lower respiratory tract in human will likely require intranasal and aerosol delivery of antigen. These results also suggest that the selection of epitope(s) to be included in the vaccine must take into account the route of inoculation