Respiratory DC Use IFITM3 to Avoid Direct Viral Infection and Safeguard Virus-Specific CD8+ T Cell Priming

Abstract

Respiratory dendritic cells (DC) play a pivotal role in the initiation of adaptive immune responses to influenza virus. To do this, respiratory DCs must ferry viral antigen from the lung to the draining lymph node without becoming infected and perishing en route. We show that respiratory DCs up-regulate the expression of the antiviral molecule, interferon-induced transmembrane protein 3 (IFITM3) in response to influenza virus infection, in a manner dependent on type I interferon signaling and the transcription factors IRF7 and IRF3. Failure of respiratory DCs to up-regulate IFITM3 following influenza virus infection resulted in impaired trafficking to the draining LN and consequently in impaired priming of an influenza-specific CD8+ T cell response. The impaired trafficking of IFITM3-deficient DC correlated with an increased susceptibility of these DC to influenza virus infection. This work shows that the expression of IFITM3 protects respiratory DCs from influenza virus infection, permitting migration from lung to LN and optimal priming of a virus specific T-cell response.

SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans

“…As IFITM3 has been reported to have roles in epithelial cells 6 , endothelial cells 39 , and dendritic cells 40 , we will explore its regulation in these cells in future studies. The current analysis indicates that the innate factor IFITM3 may play a key role in regulating the cellular response and severity of influenza infection at least in part through its expression in CD8 T-cells.…”

The IFITM protein family in adaptive immunity

“…Several distinct functions have been associated with different IFITM family members, including germ cell specification (IFITM1-IFITM3), [14][15][16]23,24 osteoblast function and bone mineralization (IFITM5), [25][26][27][28][29] and immune functions (IFITM1-3, IFITM6), 7,8,13,[30][31][32][33][34][35][36][37][38] in addition to their roles as virus-restriction factors (IFITM1-3, murine IFITM6). The IFITM proteins have also been described to play a role in cell cycle control and apoptosis and their dysregulated expression, over-expression or mutation can be associated with colon cancers and metabolic dysregulation.…”

“…7,8,38 During influenza infection, IFITM3 is upregulated in dendritic cells in the lung by type I IFN, allowing them to survive and migrate to the draining lymph node in order to present viral antigens. 38 IFITM3 is then rapidly up-regulated on T cells on their activation in the draining lymph nodes, and high IFITM3 expression is maintained because they migrate to sites of viral infection, providing a survival advantage that enables them to carry out their effector functions. 7,8 Interestingly, IFITM3 is also constitutively expressed in tissue-resident T cells in lung and airways, and also spleen, skin and brain, suggesting that it promotes their survival at these sites of potential viral infection.…”

Antiviral responses against chicken respiratory infections: Focus on avian influenza virus and infectious bronchitis virus

“…Therefore their existence is critical for the transportation of viral antigens. It has been shown that the expression of interferon-induced transmembrane protein (IFITM)3 in CD103 + DCs ensures their resistance to influenza virus infection [23]. However, some tissue-resident DCs are susceptible to influenza virus infection.…”