Defective early innate immune response to ectromelia virus in the draining lymph nodes of aged mice due to impaired dendritic cell accumulation

• Published in: Aging cell 2020-07, Vol.19 (7), p.e13170-n/a
• Main Authors: Stotesbury, Colby, Wong, Eric B., Tang, Lingjuan, Montoya, Brian, Knudson, Cory J., Melo‐Silva, Carolina R., Sigal, Luis J.
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Age; Aging; Animals; Antigens; B cells; Biological response modifiers; Cell adhesion & migration; Cell migration; chemokines; Dendritic cells; Dendritic Cells - metabolism; Disease resistance; Disease susceptibility; ectromelia virus; Ectromelia virus - immunology; Experiments; Flow cytometry; Immune response; Immune system; Immunity, Innate - immunology; Infection; Infections; Inflammation; Innate immunity; Interferon; Killer cells; Lymph nodes; Lymph Nodes - metabolism; Lymphatic system; Lymphoid cells; Mice; Monocyte chemoattractant protein 1; Monocytes; Natural killer cells; NKG2 antigen; Original Paper; Original Papers; Skin; Viral diseases; Viral infections; Virus diseases
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13170

It is known that aging decreases natural resistance to viral diseases due to dysfunctional innate and adaptive immune responses, but the nature of these dysfunctions, particularly in regard to innate immunity, is not well understood. We have previously shown that C57BL/6J (B6) mice lose their natural resistance to footpad infection with ectromelia virus (ECTV) due to impaired maturation and recruitment of natural killer (NK) cells to the draining popliteal lymph node (dLN). More recently, we have also shown that in young B6 mice infected with ECTV, the recruitment of NK cells is dependent on a complex cascade whereby migratory dendritic cells (mDCs) traffic from the skin to the dLN, where they produce CCL2 and CCL7 to recruit inflammatory monocytes (iMOs). In the dLN, mDCs also upregulate NKG2D ligands to induce interferon gamma (IFN‐γ) expression by group 1 innate lymphoid cells (G1‐ILCs), mostly NK in cells but also some ILC1. In response to the IFN‐γ, the incoming uninfected iMOs secret CXCL9 to recruit the critical NK cells. Here, we show that in aged B6 mice, the trafficking of mDCs to the dLN in response to ECTV is decreased, resulting in impaired IFN‐γ expression by G1‐ILCs, reduced accumulation of iMOs, and attenuated CXCL9 production by iMOs, which likely contributes to decrease in NK cell recruitment. Together, these data indicate that defects in the mDC response to viral infection during aging result in a reduced innate immune response in the dLN and contribute to increased susceptibility to viral disease in the aged. Stotesbury et al. show that in aged mice, the trafficking of migratory dendritic cells (mDC) to the draining lymph node (dLN) in response to viral infection is decreased. Resulting in impaired expression of IFN‐γ by Group 1 Innate Lymphoid cells, reduced accumulation of and attenuated CXCL9 production by inflammatory monocytes (iMO). As a consequence, natural killer cell recruitment to the dLN is increased and susceptibility to lethal viral disease is increased.