CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses

Abstract

Acute respiratory virus infection (ARI) induces CD8 T cells with diminished cytokine production and functional impairment. The role of cellular mediators of immune impairment, specifically CD4 regulatory T cells (Tregs), is incompletely understood in ARI. Tregs are known suppressors of effector T cell function, but whether they are detrimental or beneficial in ARI remains controversial. We show in this paper that Treg depletion leads to increased CD8 T cell function and lower virus titer in mice infected with human metapneumovirus. We further demonstrate that Tregs play a temporal role in the immune response to human metapneumovirus and influenza: Treg depletion before infection pathologically reduces virus-specific CD8 T cell numbers and delays virus clearance, whereas depletion 2 d postinoculation enhances CD8 T cell functionality without reducing virus-specific CD8 T cell numbers. Mechanistically, Treg depletion during immune priming led to impaired dendritic cell and CD8 T cell migration. Further, early Treg depletion was associated with immune skewing toward a type 2 phenotype characterized by increased type 2 innate lymphoid cells and T2 CD4 T cells, which was not observed when Treg depletion was delayed until after inoculation. These results indicate that the presence of Tregs at inoculation is critical for efficient priming of the CD8 T cell response to ARI, whereas later in infection, Tregs are dispensable for virus clearance.

Regulatory T Cells Condition Lymphatic Endothelia for Enhanced Transendothelial Migration

“…However, it is uncertain how multiple suppressive mechanisms can be coordinated and deployed to restrict such a large variety of cell types and responses. Tregs are also required for the active regulation of appropriately timed effector cell migration and immune responses (Lund et al, 2008;Rogers et al, 2018). Thus, Tregs have dual roles in suppressing and ensuring appropriate immune responses.…”

Association of immunological features with COVID-19 severity: a systematic review and meta-analysis

“…It is necessary to explore the host immune response to SARS-CoV-2, which may help to identify immune markers of disease severity for effective triage of COVID-19 patients [18]. Our study mainly compared the level differences of immune cells and cytokines between mild and severe patients with COVID-19.…”

“…CD8 + T cells exert their effects mainly through two mechanisms, including cytolytic activities against target cells and secretion of cytokines [17]. CD4 + T cells could activate the CD8 + T cell response to acute respiratory virus infection [18]. SARS-CoV-2 and associated autoimmune antibodies may lead to growth inhibition and apoptosis of hematopoiesis [19], which may decrease the production and maturation of immune cells [4].…”

Association of immunological features with COVID-19 severity: a systematic review and meta-analysis

“…It is necessary to explore the host immune response to SARS-CoV-2, which may help to identify immune markers of disease severity for effective triage of COVID-19 patients [25]. Our study mainly compared the level differences of immune cells, cytokines and chemokines between mild and severe patients with COVID-19.…”