The Role of Dendritic Cells in Promoting Adaptive Antiviral Immune Responses at the Intestinal Mucosa

The immune system of the gastrointestinal tract must be tightly regulated to limit inflammatory responses towards innocuous food and commensal antigens while allowing for rapid development of effector responses against invading pathogens. Highly specialized antigen presenting cells, such as dendritic cells (DCs), play an essential role in balancing the regulatory and inflammatory responses in the gut. Although multiple DC subsets have been described in both lymphoid and non-lymphoid tissues, we know little about which DC subset(s) provoke antiviral responses within the gut, as well as what DC-intrinsic pathways are needed for optimal CD8+ T cell responses against viral infection at the mucosa. Herein, using an infection model with rotavirus (RV), a double-stranded RNA virus with a small intestinal tropism, I demonstrated that BATF3-dependent DCs are required for generating optimal RV-specific CD8+ T-cell responses in adult mice. However, a significant amount of RV-specific CD8+ T cells are still detectable in the small intestinal lamina propria (SILP) of Batf3-/- adult mice, suggesting the existence of compensatory cross-presentation machinery in the absence of BATF3-dependent DCs. Interestingly, BATF3-dependent DCs are absolutely needed for RV-specific CD8+ T-cell responses in neonatal mice. Furthermore, a decreased Th1 response and an increased Th17 in both adult and neonatal Batf3-/- mice is observed upon RV infection, although local and systemic RV-specific immunoglobulin A (IgA) production kinetics and titers are unimpaired in these mice. Our lab previously showed that DC-intrinsic lymphotoxin beta receptor (LTbR) signaling pathway is important for optimal CD8+ T-cell expansion in responses to foreign protein antigens in the periphery. Moreover, Lta-/- mice display prolonged RV antigen shedding and delayed anti-RV IgA response. To determine whether LTbR signaling pathway in DC can impact on anti-RV adaptive immune responses, I challenged Ltbr-/- ->WT bone marrow chimeric mice with RV. I found that LTbR signaling in the radio-sensitive is dispensable for RV clearance. In Ltbr-/-->WT chimeric mice, increased interferon gamma-secreting RV-specific CD8+ T cells and polyclonal Th1 cells are present, accompanied by a decrease in interleukin 17-producing polyclonal CD4+ T cells in the SILP. In spite of this altered cytokine profile, the local and systemic RV-specific IgA response is unperturbed. Taken together, these studies contribute towards our understanding of DCs in regulating antiviral adaptive immune responses in the intestine.Ph.D