Top Reads

In this Top Read by Gao et al. (p. 1456), the authors investigated the mechanisms that regulate alveolar macrophage (AM) formation and maintenance. Specifically, they explored the role of mitochondrial transcription factor A (TFAM) in AM development, maintenance, and function. In a mouse lacking TFAM, AM numbers and maturity were significantly impaired. Furthermore, AMs lacking TFAM had lower levels of inflammation and expression of self-renewal genes compared with controls. This altered genetic program likely accounted for attenuated cellular debris clearance and increased susceptibility to influenza virus in mice lacking TFAM as compared with wild type mice. Finally, the authors showed that influenza infection of AMs led to decreased TFAM expression and mitochondrial fitness. Together, these data show that TFAM is an important factor in regulating AM homeostasis and AM responses to viral infections.

Type III IFNs (IFNLs) exert both antiviral and immunomodulatory roles in mammals. In this Top Read, Manivasagam et al. (p. 1341) investigated the role of IFNL in the mouse model of multiple sclerosis (MS), experimental autoimmune encephalitis (EAE), an autoimmune disease of the CNS. Using two different methods of eliminating this cytokine, the authors showed that IFNL limits clinical disease during EAE. Mechanistically, IFNL promotes autoreactive T cell function and axonal injury in vivo. These effects were due to enhanced Ag presentation and increased expression of IFNγ and GM-CSF by effector T cells within the CNS. The authors also examined IFNL levels in patients with MS and found elevated IFNL expression compared with controls. Furthermore, IFNL levels were higher in active versus inactive MS lesions. Altogether, these results suggest that targeting IFNL could have therapeutic potential for patients with chronic autoimmune neuroinflammation.

In this Top Read, Stutte et al. (p. 1445) demonstrated that a high-fat diet (HFD) increases plasmacytoid dendritic cell (pDC) trafficking, retention, and activation in visceral adipose tissue (VAT). Mice fed HFDs had increased numbers of pDCs, and they organized into high-density clusters within VAT. Blocking P-selectin abolished pDC migration into VAT. In addition, mice fed an HFD had a VAT cell-specific increase in expression of the P-selectin ligand, CD63E. CCR7 and α4 integrin were shown to be necessary for pDC entry into the VAT of mice fed HFDs. The VAT-associated pDCs in HFD-fed mice also produced higher levels of type I IFN compared with diet controls. Finally, P-selectin blocking Ab treatment resulted in decreased weight gain and improved glucose tolerance in mice fed HFD compared with a control diet. Together, these data demonstrated how diet can alter pDCs and provide a potential target for obesity intervention.

To better understand why humans often outgrow asthma, Hazan et al. (p. 1467) catalog the immunological differences between juvenile and adult mouse lungs in response to infection. In this Top Read, the authors show that all ages were afflicted with high viral RNA loads after Sendai virus infection. However, early in viral bronchiolitis, younger mice possessed a greater percentage of virus-infected airway cells and a cytokine expression profile that correlated with worse lung health as compared with adult mice. Furthermore, younger mice, both at baseline and after infection, had a higher number of alveolar macrophages (AMs), and these cells expressed lower surface MHC-II levels than did AMs of older mice. The amount of surface MHC-II and expression of MHC-II related genes increased with age in AMs but not in other immune cell types. Both surface MHC-II and MHC-II related gene expression in AM continued to increase as the mice aged, but plateaued by 7 mo, indicating that AMs were functionally maturing, not dying over time. Importantly, these data align with the authors’ separate observation that COVID-19-inspired lockdown measures, which were previously shown to reduce incidence of respiratory disease caused by viruses other than SARS-CoV-2, also erased the typical age-dependent trends in virus-induced asthma attacks in humans. Altogether, the data suggest that children’s regular exposure to endemic respiratory viruses trains their AMs as they age, which causes them to outgrow asthma as they get older.

In this top read, Dwivedi et al. (p. 1406) establish anti–IL-10 receptor Ab (anti–IL-10R1) as an effective adjuvant for the Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine. A single dose of the BCG vaccine with anti–IL-10R1 (BCG/anti–IL-10R1) resulted in more central memory T cells and reduced proinflamatory cytokine levels in the lung for up to 7 wk after vaccination. In vitro, lung mononuclear cells from BCG/anti–IL-10R1 mice produced increased levels of IFN-γ, IL-17, and TNF-α when stimulated with M. tuberculosis–specific Ag. Challenge of the BCG/anti–IL-10R1–immunized mice with M. tuberculosis showed extended protection and survival as compared with vaccine control mice. Altogether, the data suggest that blocking IL-10 signaling at the time of BCG vaccination will dramatically increase vaccine efficacy and provide enhanced protection against TB.