IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

Abstract

The pro- and anti-inflammatory pathways that determine the balance of inflammation and viral control during SARS-CoV-2 infection are not well understood. Here we examine the roles of IFNγ and IL-10 in regulating inflammation, immune cell responses and viral replication during SARS-CoV-2 infection of rhesus macaques. IFNγ blockade tended to decrease lung inflammation based on 18FDG-PET/CT imaging but had no major impact on innate lymphocytes, neutralizing antibodies, or antigen-specific T cells. In contrast, IL-10 blockade transiently increased lung inflammation and enhanced accumulation of virus-specific T cells in the lower airways. However, IL-10 blockade also inhibited the differentiation of virus-specific T cells into airway CD69+CD103+ TRM cells. While virus-specific T cells were undetectable in the nasal mucosa of all groups, IL-10 blockade similarly reduced the frequency of total TRM cells in the nasal mucosa. Neither cytokine blockade substantially affected viral load and infection ultimately resolved. Thus, in the macaque model of mild COVID-19, the pro- and anti-inflammatory effects of IFNγ and IL-10 have no major role in control of viral replication. However, IL-10 has a key role in suppressing the accumulation of SARS-CoV-2-specific T cells in the lower airways, while also promoting TRM at respiratory mucosal surfaces.

Pre-existing interferon gamma conditions the lung to mediate early control of SARS-CoV-2

“…However, IFNγ does not appear to play a role during the natural course of SCV2 infection since as shown here animals deficient in IFNγ receptor signaling do not display impaired viral control in the absence of BCG. This conclusion is in agreement with previous findings in both mice (25,60) and rhesus macaques (61). Furthermore, while deficiencies in IFNγ signaling have been characterized in humans and linked with increased susceptibility to some viral pathogens (62), there is little evidence associating such mutations with increased risk of COVID-19 despite intensive investigation in this area.…”

Th2 and Th17‐associated immunopathology following SARS‐CoV‐2 breakthrough infection in Spike‐vaccinated ACE2‐humanized mice

“…On the other hand, during acute respiratory viral infection such as influenza, Foxp3‐negative T cells (type 1 regulatory T cells and CD8 + T cells) are major contributors to IL‐10 production in the airway 53 . In the lungs of nonhuman primate models, IL‐10 suppresses T cell expansion but promote tissue‐resident memory T cell development during SARS‐CoV‐2 infection 54 . It is possible that Spike vaccination with Alum/CpG primes T cell differentiation in which IL‐10‐producing regulatory T cells are less favored.…”

“…53 In the lungs of nonhuman primate models, IL-10 suppresses T cell expansion but promote tissue-resident memory T cell development during SARS-CoV-2 infection. 54…”

Tissue‐resident memory T cells and lung immunopathology

“…The release of another anti‐inflammatory cytokine, IL‐10, also enhanced TGF‐β expression, thus promoting early commitment of effector T cells to the T RM cell lineage 53 . IL‐10 was shown to suppress early effector T‐cell expansion and acute inflammation, while promoting CD8 + T RM formation during SARS‐CoV‐2 infection in rhesus macaques 54 . Interestingly, a major source of IL‐10 during respiratory viral infections is effector CD8 + T cell themselves, 6,55 indicating autocrine CD8 + T cell IL‐10 signaling may also contribute to CD8 + T RM responses.…”

“…53 IL-10 was shown to suppress early effector T-cell expansion and acute inflammation, while promoting CD8 + T RM formation during SARS-CoV-2 infection in rhesus macaques. 54 Interestingly, a major source of IL-10 during respiratory viral infections is effector CD8 + T cell themselves, 6,55 indicating autocrine CD8 + T cell IL-10 signaling may also contribute to CD8 + T RM responses. IL-15 is considered a central regulator of memory CD8 + T cells, but T RM cells were believed to be less dependent on IL-15 for maintenance in vivo.…”