Abstract
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.
Highlights
It is known that aging negatively affects the ability of the host immune system to respond to viral infections (Nikolich-Zugich, 2018)
We have shown that in young B6 mice infected with ectromelia virus (ECTV), the recruitment of natural killer (NK) cells is dependent on a complex cascade whereby migratory dendritic cells traffic from the skin to the draining popliteal lymph node (dLN), where they produce CCL2 and CCL7 to recruit inflammatory monocytes
We have previously identified an indispensable innate immune cascade against ECTV, whereby migratory dendritic cells (mDCs) migrate to the dLN as early as 24 hpi, to recruit inflammatory monocytes (iMOs) via CCL2/CCL7, and upregulate NKG2D ligands to induce IFN-γ expression in group 1 innate lymphoid cells (G1-ILCs)
Summary
It is known that aging negatively affects the ability of the host immune system to respond to viral infections (Nikolich-Zugich, 2018). In a series of papers, we have previously shown an intricate network of collaborative innate immune responses within the dLN that lead to the control and, resolution of ECTV infection in young B6 mice (Fang, Roscoe, & Sigal, 2010; Wong et al, 2018; Xu et al, 2015) Within this inflammatory network, skin mDCs (CD11c+ MHC IIhi), play a central organizing role. While as expected (Wong, Montoya, Stotesbury, et al, 2019), the number of mDCs increased significantly in the dLNs of young mice at 24 hpi (Figure 1g) and 48 hpi (Figure 1h), these increases were not observed in aged mice, suggesting early defective migration of mDCs to the dLN of aged mice in response to virulent ECTV infection. When compared to the dLN of young mice, the dLN of aged mice infected with ECTVΔ166 had decreased upregulation of Ccl, Ccl, and Ifng at 24 hpi (Figure 5a–c), and at 60 hpi, increased viral transcripts, decreased upregulation of Cxcl, and reduced accumulation iMOs 81.7
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