Adenovirus serotype 35: Multiple mechanisms of immune modulation
Buntzman, Adam Scott
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Adenoviruses (Ads) persist in human T cells in vivo. However, studying most Ad serotypes in lymphocytes is hampered by poor infectivity in vitro, due to low Coxsackie-Adenovirus Receptor expression. Therefore, host immune evasion has been studied in non-leukocytes, where immunorepression was postulated to be caused by the immunomodulatory E3 region. Ad35 efficiently infects lymphocytes in vitro by utilizing CD46 for cell entry, thus we postulated that Ad35 would allow us to study the E3 region in leukocytes. In addition, CD46 receptor signaling is known to induce Tr1 regulatory T cells, repress dendritic cells (DCs), induce B cell IgE class switch and protect cells against complement destruction. Therefore, we hypothesized that Ad35-induced CD46 signaling would lead to these immune perturbations as well. We found that the Ad35 E3 region functions in non-lymphoid cells to block TNF signal transduction and apoptosis by downregulating TNF receptors. Despite high infectivity, Ad35 E3 proteins and their functions were not observed in T cells. However, T cell receptor crosslinking during Ad35 infection induced Tr1 regulatory T cells, as demonstrated by the upregulation of CD25, IL-10, IFNgamma, FoxP3, perforin, granzyme B, and the appearance of the characteristic Tr1 cell morphology. In addition, Ad35 induced a partial maturation of DCs, as shown by the upregulation of CD86 and class II MHC with a lack of IL-12 expression. Ad35 also downregulated CD46 and rendered cells susceptible to complement killing. Like Ad5, the E3 proteins from Ad35 can block TNF killing in non-lymphoid cells. However, Ad35 has the emergent property of CD46 usage that allows for additional modulatory functions in immune cells as well. The Tr1 cell induction and the repression of full DC maturation may explain the dampened immune responses seen with the group B Ads, whereas the downregulation of the CD46 receptor may contribute to the urinary tract pathology observed in patients infected with Ad35 or may lead to immune cell depletion. Our observations may influence the use of the group B Ads as gene therapy and vaccine therapy vectors, and may yield insight into how Ad35 evades the host immune responses to establish latency.
- Theses and Dissertations